Azolo triazines and pyrimidines

ABSTRACT

Corticotropin releasing factor (CRF) antagonists of formula I or II: 
                         
and their use in treating anxiety, depression, and other psychiatric, neurological disorders as well as treatment of immunological, cardiovascular or heart-related diseases and colonic hypersensitivity associated with psychopathological disturbance and stress.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of Ser. No. 09/930,782, filed on Aug. 16, 2001 now abandoned, which is a divisional of Ser. No. 09/014,734, filed Jan. 28, 1998, now U.S. Pat. No. 6,313,124, and claims benefit of Ser. No. 60/023,290, filed Jul. 24, 1996, the contents all of which are incorporated herein by reference.

FIELD OF THE INVENTION

This invention relates a treatment of psychiatric disorders and neurological diseases including major depression, anxiety-related disorders, post-traumatic stress disorder, supranuclear palsy and feeding disorders as well as treatment of immunological, cardiovascular or heart-related diseases and colonic hypersensitivity associated with psychopathological disturbance and stress, by administration of certain [1,5-a]pyrazolo-1,3,5-triazines, [1,5-a]-1,2,3-triazolo-1,3,5-triazines, [1,5-a]-pyrazolo-pyrimidines and [1,5-a]-1,2,3-triazolo-pyrimidines.

BACKGROUND OF THE INVENTION

Corticotropin releasing factor (herein referred to as CRF), a 41 amino acid peptide, is the primary physiological regulator of proopiomelanocortin(POMC)-derived peptide secretion from the anterior pituitary gland [J. Rivier et al., Proc. Nat. Acad. Sci. (USA) 80:4851 (1983); W. Vale et al., Science 213:1394 (1981)]. In addition to its endocrine role at the pituitary gland, immunohistochemical localization of CRF has demonstrated that the hormone has a broad extrahypothalamic distribution in the central nervous system and produces a wide spectrum of autonomic, electrophysiological and behavioral effects consistent with a neurotransmitter or neuromodulator role in brain [W. Vale et al., Rec. Prog. Horm. Res. 39:245 (1983); G. F. Koob, Persp. Behav. Med. 2:39 (1985); E. B. De Souza et al., J. Neurosci. 5:3189 (1985)]. There is also evidence that CRF plays a significant role in integrating the response of the immune system to physiological, psychological, and immunological stressors [J. E. Blalock, Physiological Reviews 69:1 (1989); J. E. Morley, Life Sci. 41:527 (1987)].

Clinical data provide evidence that CRF has a role in psychiatric disorders and neurological diseases including depression, anxiety-related disorders and feeding disorders. A role for CRF has also been postulated in the etiology and pathophysiology of Alzheimer's disease, Parkinson's disease, Huntington's disease, progressive supranuclear palsy and amyotrophic lateral sclerosis as they relate to the dysfunction of CRF neurons in the central nervous system [for review see E. B. De Souza, Hosp. Practice 23:59 (1988)].

In affective disorder, or major depression, the concentration of CRF is significantly increased in the cerebral spinal fluid (CSF) of drug-free individuals [C. B. Nemeroff et al., Science 226:1342 (1984); C. M. Banki et al., Am. J. Psychiatry 144:873 (1987); R. D. France et al., Biol. Psychiatry 28:86 (1988); M. Arato et al., Biol Psychiatry 25:355 (1989)]. Furthermore, the density of CRF receptors is significantly decreased in the frontal cortex of suicide victims, consistent with a hypersecretion of CRF [C. B. Nemeroff et al., Arch. Gen. Psychiatry 45:577 (1988)]. In addition, there is a blunted adrenocorticotropin (ACTH) response to CRF (i.v. administered) observed in depressed patients [P. W. Gold et al., Am J. Psychiatry 141:619 (1984); F. Holsboer et al., Psychoneuroendocrinology 9:147 (1984); P. W. Gold et al., New Eng. J. Med. 314:1129 (1986)]. Preclinical studies in rats and non-human primates provide additional support for the hypothesis that hypersecretion of CRF may be involved in the symptoms seen in human depression [R. M. Sapolsky, Arch. Gen. Psychiatry 46:1047 (1989)]. There is preliminary evidence that tricyclic antidepressants can alter CRF levels and thus modulate the numbers of CRF receptors in brain [Grigoriadis et al., Neuropsychopharmacology 2:53 (1989)].

There has also been a role postulated for CRF in the etiology of anxiety-related disorders. CRF produces anxiogenic effects in animals and interactions between benzodiazepine/non-benzodiazepine anxiolytics and CRF have been demonstrated in a variety of behavioral anxiety models [D. R. Britton et al., Life Sci. 31:363 (1982); C. W. Berridge and A. J. Dunn Regul. Peptides 16:83 (1986)]. Preliminary studies using the putative CRF receptor antagonist a-helical ovine CRF (9-41) in a variety of behavioral paradigms demonstrate that the antagonist produces “anxiolytic-like” effects that are qualitatively similar to the benzodiazepines [C. W. Berridge and A. J. Dunn Horm. Behav. 21:393 (1987), Brain Research Reviews 15:71 (1990)]. Neurochemical, endocrine and receptor binding studies have all demonstrated interactions between CRF and benzodiazepine anxiolytics providing further evidence for the involvement of CRF in these disorders. Chlordiazepoxide attenuates the “anxiogenic” effects of CRF in both the conflict test [K. T. Britton et al., Psychopharmacology 86:170 (1985); K. T. Britton et al., Psychopharmacology 94:306 (1988)] and in the acoustic startle test [N. R. Swerdlow et al., Psychopharmacology 88:147 (1986)] in rats. The benzodiazepine receptor antagonist (Ro15-1788), which was without behavioral activity alone in the operant conflict test, reversed the effects of CRF in a dose-dependent manner while the benzodiazepine inverse agonist (FG7142) enhanced the actions of CRF [K. T. Britton et al., Psychopharmacology 94:306 (1988)].

The mechanisms and sites of action through which the standard anxiolytics and antidepressants produce their therapeutic effects remain to be elucidated. It has been hypothesized however, that they are involved in the suppression of the CRF hypersecretion that is observed in these disorders. Of particular interest is that preliminary studies examining the effects of a CRF receptor antagonist (α-helical CRF₉₋₄₁) in a variety of behavioral paradigms have demonstrated that the CRF antagonist produces “anxiolytic-like” effects qualitatively similar to the benzodiazepines [for review see G. F. Koob and K. T. Britton, In: Corticotropin-Releasing Factor: Basic and Clinical Studies of a Neuropeptide, E. B. De Souza and C. B. Nemeroff eds., CRC Press p221 (1990)].

Several publications describe corticotropin releasing factor antagonist compounds and their use to treat psychiatric disorders and neurological diseases. Examples of such publications include DuPont Merck PCT application US94/11050, Pfizer WO 95/33750, Pfizer WO 95/34563, Pfizer WO 95/33727 and Pfizer EP 0778 277 A1.

Insofar as is known, [1,5-a]-pyrazolo-1,3,5-triazines, [1,5-a]-1,2,3-triazolo-1,3,5-triazines, [1,5-a]-pyrazolo-pyrimidines and [1,5-a]1,2,3-triazolo-pyrimidines, have not been previously reported as corticotropin releasing factor antagonist compounds useful in the treatment of psychiatric disorders and neurological diseases. However, there have been publications which teach some of these compounds for other uses.

For instance, EP 0 269 859 (Ostuka, 1988) discloses pyrazolotriazine compounds of the formula:

where R¹ is OH or alkanoyl, R² is H, OH, or SH, and R³ is an unsaturated heterocyclic group, naphthyl or substituted phenyl, and states that the compounds have xanthine oxidase inhibitory activity and are useful for treatment of gout.

EP 0 594 149 (Ostuka, 1994) discloses pyrazolotriazine and pyrazolopyrimidine compounds of the formula:

where A is CH or N, R⁰ and R³ are H or alkyl, and R¹ and R² are H, alkyl, alkoxyl, alkylthio, nitro, etc., and states that the compounds inhibit androgen and are useful in treatment of benign prostatic hypertrophy and prostatic carcinoma.

U.S. Pat. No. 3,910,907 (ICI, 1975) discloses pyrazolotriazines of the formula:

where R1 is CH₃, C₂H₅ or C₆H₅, X is H, C₆H₅, m-CH₃C₆H₄, CN, COOEt, Cl, I or Br, Y is H, C₆H₅, o-CH₃C₆H₄, or p-CH₃C₆H₄, and Z is OH, H, CH₃, C₂H₅, C₆H₅, n-C₃H₇, i-C₃H₇, SH, SCH₃, NHC₄H₉, or N(C₂H₅)₂, and states that the compounds are c-AMP phosphodiesterase inhibitors useful as bronchodilators.

U.S. Pat. No. 3,995,039 discloses pyrazolotriazines of the formula:

where R¹ is H or alkyl, R² is H or alkyl, R³ is H, alkyl, alkanoyl, carbamoyl, or lower alkylcarbamoyl, and R is pyridyl, pyrimidinyl, or pyrazinyl, and states that the compounds are useful as bronchodilators.

U.S. Pat. No. 5,137,887 discloses pyrazolotriazines of the formula:

where R is lower alkoxy, and teaches that the compounds are xanthine oxidase inhibitors and are useful for treatment of gout.

U.S. Pat. No. 4,892,576 discloses pyrazolotriazines of the formula:

where X is O or S, Ar is a phenyl, naphthyl, pyridyl or thienyl group, R₆–R₈ are H, alkyl, etc., and R₉ is H, alkyl, phenyl, etc. The patent states that the compounds are useful as herbicides and plant growth regulants.

U.S. Pat. No. 5,484,760 and WO 92/10098 discloses herbicidal compositions containing, among other things, a herbicidal compound of the formula:

where A can be N, B can be CR₃, R₃ can be phenyl or substituted phenyl, etc., R is —N(R₄)SO₂R₅ or —SO₂N(R₆)R₇ and R₁ and R₂ can be taken together to form

where X, Y and Z are H, alkyl, acyl, etc. and D is O or S.

U.S. Pat. No. 3,910,907 and Senga et al., J. Med. Chem., 1982, 25, 243–249, disclose triazolotriazines cAMP phosphodiesterase inhibitors of the formula:

where Z is H, OH, CH₃, C₂H₅, C₆H₅, n-C₃H₇, iso-C₃H₇, SH, SCH₃, NH(n-C₄H₉), or N(C₂H₅)₂, R is H or CH₃, and R₁ is CH₃ or C₂H₅. The reference lists eight therapeutic areas where inhibitors of cAMP phosphodiesterase could have utility: asthma, diabetes mellitus, female fertility control, male infertility, psoriasis, thrombosis, anxiety, and hypertension.

WO95/35298 (Otsuka, 1995) discloses pyrazolopyrimidines and states that they are useful as analgesics. The compounds are represented by the formula:

where Q is carbonyl or sulfonyl, n is 0 or 1, A is a single bond, alkylene or alkenylene, R¹ is H, alkyl, etc., R² is naphthyl, cycloalkyl, heteroaryl, substituted phenyl or phenoxy, R³ is H, alkyl or phenyl, R⁴ is H, alkyl, alkoxycarbonyl, phenylalkyl, optionally phenylthio-substituted phenyl, or halogen, R⁵ and R⁶ are H or alkyl.

EP 0 591 528 (Otsuka, 1991) discloses antiinflammatory use of pyrazolopyrimidines represented by the formula:

where R₁, R₂, R₃ and R₄ are H, carboxyl, alkoxycarbonyl, optionally substituted alkyl, cycloalkyl, or phenyl, R₅ is SR₆ or NR₇R₈, R₆ is pyridyl or optionally substituted phenyl, and R₇ and R₈ are H or optionally substituted phenyl.

Springer et al, J. Med. Chem., 1976, vol. 19, no. 2, 291–296 and Springer U.S. Pat. Nos. 4,021,556 and 3,920,652 disclose pyrazolopyrimidines of the formula:

where R can be phenyl, substituted phenyl or pyridyl, and their use to treat gout, based on their ability to inhibit xanthine oxidase.

Joshi et al., J. Prakt. Chemie, 321, 2, 1979, 341–344, discloses compounds of the formula:

where R¹ is CF₃, C₂F₅, or C₆H₄F, and R² is CH₃, C₂H₅, CF₃, or C₆H₄F.

Maquestiau et al., Bull. Soc. Belg., vol. 101, no. 2, 1992, pages 131–136 discloses a pyrazolo[1,5-a]pyrimidine of the formula:

Ibrahim et al., Arch. Pharm. (weinheim) 320, 487–491 (1987) discloses pyrazolo[1,5-a]pyrimidines of the formula:

where R is NH2 or OH and Ar is 4-phenyl-3-cyano-2-aminopyrid-2-yl.

Other references which disclose azolopyrimidines inclued EP 0 511 528 (Otsuka, 1992), U.S. Pat. No. 4,997,940 (Dow, 1991), EP 0 374 448 (Nissan, 1990), U.S. Pat. No. 4,621,556 (ICN, 1997), EP 0 531 901 (Fujisawa, 1993), U.S. Pat. No. 4,567,263 (BASF, 1986), EP 0 662 477 (Isagro, 1995), DE 4 243 279 (Bayer, 1994), U.S. Pat. No. 5,397,774 (Upjohn, 1995), EP 0 521 622 (Upjohn, 1993), WO 94/109017 (Upjohn, 1994), J. Med. Chem., 24, 610–613 (1981), and J. Het. Chem., 22, 601 (1985).

SUMMARY OF THE INVENTION

In accordance with one aspect, the present invention provides novel compounds, pharmaceutical compositions and methods which may be used in the treatment of affective disorder, anxiety, depression, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal disease, anorexia nervosa or other feeding disorder, drug or alcohol withdrawal symptoms, drug addiction, inflammatory disorder, fertility problems, disorders, the treatment of which can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, or a disorder selected from inflammatory disorders such as rheumatoid arthritis and osteoarthritis, pain, asthma, psoriasis and allergies; generalized anxiety disorder; panic, phobias, obsessive-compulsive disorder; post-traumatic stress disorder; sleep disorders induced by stress; pain perception such as fibromyalgia; mood disorders such as depression, including major depression, single episode depression, recurrent depression, child abuse induced depression, and postpartum depression; dysthemia; bipolar disorders; cyclothymia; fatigue syndrome; stress-induced headache; cancer, human immunodeficiency virus (HIV) infections; neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and Huntington's disease; gastrointestinal diseases such as ulcers, irritable bowel syndrome, Crohn's disease, spastic colon, diarrhea, and post operative ilius and colonic hypersensitivity associated by psychopathological disturbances or stress; eating disorders such as anorexia and bulimia nervosa; hemorrhagic stress; stress-induced psychotic episodes; euthyroid sick syndrome; syndrome of inappropriate antidiarrhetic hormone (ADH); obesity; infertility; head traumas; spinal cord trauma; ischemic neuronal damage (e.g., cerebral ischemia such as cerebral hippocampal ischemia); excitotoxic neuronal damage; epilepsy; cardiovascular and hear related disorders including hypertension, tachycardia and congestive heart failure; stroke; immune dysfunctions including stress induced immune dysfunctions (e.g., stress induced fevers, porcine stress syndrome, bovine shipping fever, equine paroxysmal fibrillation, and dysfunctions induced by confinement in chickens, sheering stress in sheep or human-animal interaction related stress in dogs); muscular spasms; urinary incontinence; senile dementia of the Alzheimer's type; multiinfarct dementia; amyotrophic lateral sclerosis; chemical dependencies and addictions (e.g., dependencies on alcohol, cocaine, heroin, benzodiazepines, or other drugs); drug and alcohol withdrawal symptoms; osteoporosis; psychosocial dwarfism and hypoglycemia in a mammal.

The present invention provides novel compounds which bind to corticotropin releasing factor receptors, thereby altering the anxiogenic effects of CRF secretion. The compounds of the present invention are useful for the treatment of psychiatric disorders and neurological diseases, anxiety-related disorders, post-traumatic stress disorder, supranuclear palsy and feeding disorders as well as treatment of immunological, cardiovascular or heart-related diseases and colonic hypersensitivity associated with psychopathological disturbance and stress in a mammal.

According to another aspect, the present invention provides novel compounds of Formulae (1) and (2) (described below) which are useful as antagonists of the corticotropin releasing factor. The compounds of the present invention exhibit activity as corticotropin releasing factor antagonists and appear to suppress CRF hypersecretion. The present invention also includes pharmaceutical compositions containing such compounds of Formulae (1) and (2), and methods of using such compounds for the suppression of CRF hypersecretion, and/or for the treatment of anxiogenic disorders.

According to yet another aspect of the invention, the compounds provided by this invention (and especially labelled compounds of this invention) are also useful as standards and reagents in determining the ability of a potential pharmaceutical to bind to the CRF receptor.

DETAILED DESCRIPTION OF INVENTION

The present invention comprises a method of treating affective disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other feeding disorder, drug addiction, drug or alcohol withdrawal symptoms, inflammatory diseases, cardiovascular or heart-related diseases, fertility problems, human immunodeficiency virus infections, hemorrhagic stress, obesity, infertility, head and spinal cord traumas, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis, hypoglycemia or a disorder the treatment of which can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, in mammals comprising administering to the mammal a therapeutically effective amount of a compound of Formulae (1) or (2):

and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof, wherein:

-   A is N or CR; -   Z is N or CR²; -   Ar is selected from phenyl, naphthyl, pyridyl, pyrimidinyl,     triazinyl, furanyl, thienyl, benzothienyl, benzofuranyl,     2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, indanyl,     1,2-benzopyranyl, 3,4-dihydro-1,2-benzopyranyl, tetralinyl, each Ar     optionally substituted with 1 to 5 R⁴ groups and each Ar is attached     to an unsaturated carbon atom; -   R is independently selected at each occurrence from H, C₁–C₄ alkyl,     C₂–C₄ alkenyl, C₂–C₄ alkynyl, C₃–C₆ cycloalkyl, C₄–C₇     cycloalkylalkyl, halo, CN, C₁–C₄ haloalkyl; -   R¹ is independently selected at each occurrence from H, C₁–C₄ alkyl,     C₂–C₄ alkenyl, C₂–C₄ alkynyl, halo, CN, C₁–C₄ haloalkyl, C₁–C₁₂     hydroxyalkyl, C₂–C₁₂ alkoxyalkyl, C₂–C₁₀ cyanoalkyl, C₃–C₆     cycloalkyl, C₄–C₁₀ cycloalkylalkyl, NR⁹R¹⁰, C₁–C₄ alkyl-NR⁹R¹⁰,     NR⁹COR¹⁰, OR¹¹, SH or S(O)_(n)R¹²; -   R² is selected from H, C₁–C₄ alkyl, C₂–C₄ alkenyl, C₂–C₄ alkynyl,     C₃–C₆ cycloalkyl, C₄–C₁₀ cycloalkylalkyl, C₁–C₄ hydroxyalkyl, halo,     CN, —NR⁶R⁷, NR⁹COR¹⁰, —NR⁶S(O)_(n)R⁷, S(O)_(n)NR⁶R⁷, C₁–C₄     haloalkyl, —OR⁷, SH or —S(O)_(n)R¹²; -   R³ is selected from:     -   —H, OR⁷, SH, S(O)_(n)R¹³, COR⁷, CO₂R⁷, OC(O)R¹³, NR⁸COR⁷,         N(COR⁷)₂, NR⁸CONR⁶R⁷, NR⁸CO₂R¹³, NR⁶R⁷, NR^(6a)R^(7a), N(OR⁷)R⁶,         CONR⁶R⁷, aryl, heteroaryl and heterocyclyl, or     -   —C₁–C₁₀ alkyl, C₂–C₁₀ alkenyl, C₂–C₁₀ alkynyl, C₃–C₈ cycloalkyl,         C₅–C₈ cycloalkenyl, C₄–C₁₂ cycloalkylalkyl or C₆–C₁₀         cycloalkenylalkyl, each optionally substituted with 1 to 3         substituents independently selected at each occurrence from         C₁–C₆ alkyl, C₃–C₆ cycloalkyl, halo, C₁–C₄ haloalkyl, cyano,         OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵,         N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl,         heteroaryl and heterocyclyl; -   R⁴ is independently selected at each occurrence from: C₁–C₁₀ alkyl,     C₂–C₁₀ alkenyl, C₂–C₁₀ alkynyl, C₃–C₆ cycloalkyl, C₄–C₁₂     cycloalkylalkyl, NO₂, halo, CN, C₁–C₄ haloalkyl, NR⁶R⁷, NR⁸COR⁷,     NR⁸CO₂R⁷, COR⁷, OR⁷, CONR⁶R⁷, CO(NOR⁹)R⁷, CO₂R⁷, or S(O)_(n)R⁷,     where each such C₁–C₁₀ alkyl, C₂–C₁₀ alkenyl, C₂–C₁₀ alkynyl, C₃–C₆     cycloalkyl and C₄–C₁₂ cycloalkylalkyl are optionally substituted     with 1 to 3 substituents independently selected at each occurrence     from C₁–C₄ alkyl, NO₂, halo, CN, NR⁶R⁷, NR⁸COR⁷, NR⁸CO₂R⁷, COR⁷ OR⁷,     CONR⁶R⁷, CO₂R⁷, CO(NOR⁹)R⁷, or S(O)_(n)R⁷; -   R⁶ and R⁷, R^(6a) and R^(7a) are independently selected at each     occurrence from:     -   —H,     -   —C₁–C₁₀ alkyl, C₃–C₁₀ alkenyl, C₃–C₁₀alkynyl, C₁–C₁₀ haloalkyl         with 1–10 halogens, C₂–C₈ alkoxyalkyl, C₃–C₆ cycloalkyl, C₄–C₁₂         cycloalkylalkyl, C₅–C₁₀ cycloalkenyl, or C₆–C₁₄         cycloalkenylalkyl, each optionally substituted with 1 to 3         substituents independently selected at each occurrence from         C₁–C₆ alkyl, C₃–C₆ cycloalkyl, halo, C₁–C₄ haloalkyl, cyano,         OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵,         N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl,         heteroaryl or heterocyclyl,     -   -aryl, aryl(C₁–C₄ alkyl), heteroaryl, heteroaryl(C₁–C₄ alkyl),         heterocyclyl or heterocyclyl(C₁–C₄ alkyl);         alternatively, NR⁶R⁷ and NR^(6a)R^(7a) are independently         piperidine, pyrrolidine, piperazine, N-methylpiperazine,         morpholine or thiomorpholine, each optionally substituted with         1–3 C₁–C₄ alkyl groups; -   R⁸ is independently selected at each occurrence from H or C₁–C₄     alkyl; -   R⁹ and R¹⁰ are independently selected at each occurrence from H,     C₁–C₄ alkyl, or C₃–C₆ cycloalkyl; -   R¹¹ is selected from H, C₁–C₄ alkyl, C₁–C₄ haloalkyl, or C₃–C₆     cycloalkyl; -   R¹² is C₁–C₄ alkyl or C₁–C₄ haloalkyl; -   R¹³ is selected from C₁–C₄ alkyl, C₁–C₄ haloalkyl, C₂–C₈     alkoxyalkyl, C₃–C₆ cycloalkyl, C₄–C₁₂ cycloalkylalkyl, aryl,     aryl(C₁–C₄ alkyl)-, heteroaryl or heteroaryl(C₁–C₄ alkyl)-; -   R¹⁴ is selected from C₁–C₁₀ alkyl, C₃–C₁₀ alkenyl, C₃–C₁₀ alkynyl,     C₃–C₈ cycloalkyl, or C₄–C₁₂ cycloalkylalkyl, each optionally     substituted with 1 to 3 substituents independently selected at each     occurrence from C₁–C₆ alkyl, C₃–C₆ cycloalkyl, halo, C₁–C₄     haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹⁵, COR¹⁵, CO₂R¹⁵, OC(O)R¹⁵,     NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹⁵, NR¹⁶R¹⁵, CONR¹⁶R¹⁵,     and C₁–C₆ alkylthio, C₁–C₆ alkylsulfinyl and C₁–C₆ alkylsulfonyl; -   R¹⁵ and R¹⁶ are independently selected at each occurrence from H,     C₁–C₆ alkyl, C₃–C₁₀ cycloalkyl, C₄–C₁₆ cycloalkylalkyl, except that     for S(O)_(n)R¹⁵, R¹⁵ cannot be H; -   aryl is phenyl or naphthyl, each optionally substituted with 1 to 5     substituents independently selected at each occurrence from C₁–C₆     alkyl, C₃–C₆ cycloalkyl, halo, C₁–C₄ haloalkyl, cyano, OR¹⁵, SH,     S(O)_(n)R¹⁵, COR¹⁵, CO₂R¹⁵, OC(O)R¹⁵, NR⁸COR¹⁵, N(COR¹⁵)₂,     NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹⁵, NR¹⁶R¹⁵, and CONR¹⁶R¹⁵; -   heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, pyranyl,     quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl,     pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl,     isoxazolyl, pyrazolyl, 2,3-dihydrobenzothienyl or     2,3-dihydrobenzofuranyl, each being optionally substituted with 1 to     5 substituents independently selected at each occurrence from C₁–C₆     alkyl, C₃–C₆ cycloalkyl, halo, C₁–C₄ haloalkyl, cyano, OR¹⁵, SH,     S(O)_(n)R¹⁵, —COR¹⁵, CO₂R¹⁵, OC(O)R¹⁵, NR⁸COR¹⁵, N(COR¹⁵)₂,     NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹⁵, NR¹⁶R¹⁵, and CONR¹⁶R¹⁵; heterocyclyl is     saturated or partially saturated -   heteroaryl, optionally substituted with 1 to 5 substituents     independently selected at each occurrence from C₁–C₆ alkyl, C₃–C₆     cycloalkyl, halo, C₁–C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹⁵,     COR¹⁵, CO₂R¹⁵, OC(O)R¹⁵, NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵,     NR⁸CO₂R¹⁵, NR¹⁵R¹⁶, and CONR¹⁶R¹⁵; -   n is independently at each occurrence 0, 1 or 2.

Preferred methods of the present invention are methods in wherein in the compound of Formulae (1) or (2), Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, each optionally substituted with 1 to 4 R⁴ substituents.

Further preferred methods of the above invention are methods wherein, in the compound of Formulae (1) or (2), A is N, Z is CR², Ar is 2,4-dichlorophenyl, 2,4-dimethylphenyl or 2,4,6-trimethylphenyl, R¹ and R² are CH₃, and R³ is NR^(6a)R^(7a).

The present invention comprises compounds of Formulae (1) or (2):

and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein:

-   A is N or CR; -   Z is N or CR²; -   Ar is selected from phenyl, naphthyl, pyridyl, pyrimidinyl,     triazinyl, furanyl, thienyl, benzothienyl, benzofuranyl,     2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, indanyl,     1,2-benzopyranyl, 3,4-dihydro-1,2-benzopyranyl, tetralinyl, each Ar     optionally substituted with 1 to 5 R⁴ groups and each Ar is attached     to an unsaturated carbon atom; -   R is independently selected at each occurrence from H, C₁–C₄ alkyl,     C₂–C₄ alkenyl, C₂–C₄ alkynyl, C₃–C₆ cycloalkyl, C₄–C₇     cycloalkylalkyl, halo, CN, C₁–C₄ haloalkyl; -   R¹ is independently selected at each occurrence from H, C₁–C₄ alkyl,     C₂–C₄ alkenyl, C₂–C₄ alkynyl, halo, CN, C₁–C₄ haloalkyl, C₁–C₁₂     hydroxyalkyl, C₂–C₁₂ alkoxyalkyl, C₂–C₁₀ cyanoalkyl, C₃–C₆     cycloalkyl, C₄–C₁₀ cycloalkylalkyl, NR⁹R¹⁰, C₁–C₄ alkyl-NR⁹R¹⁰,     NR⁹COR¹⁰, OR¹¹, SH or S(O)_(n)R¹²; -   R² is selected from H, C₁–C₄ alkyl, C₂–C₄ alkenyl, C₂–C₄ alkynyl,     C₃–C₆ cycloalkyl, C₄–C₁₀ cycloalkylalkyl, C₁–C₄ hydroxyalkyl, halo,     CN, —NR⁶R⁷, NR⁹COR¹⁰, —NR⁶S(O)_(n)R⁷, S(O)_(n)NR⁶R⁷, C₁–C₄     haloalkyl, —OR⁷, SH or —S(O)_(n)R¹²; -   R³ is selected from:     -   —H, OR⁷, SH, S(O)_(n)R¹³, COR⁷, CO₂R⁷, OC(O)R¹³, NR⁸COR⁷,         N(COR⁷)₂, NR⁸CONR⁶R⁷, NR⁸CO₂R¹³, NR⁶R⁷, NR^(6a)R^(7a), N(OR⁷)R⁶,         CONR⁶R⁷, aryl, heteroaryl and heterocyclyl, or     -   —C₁–C₁₀ alkyl, C₂–C₁₀ alkenyl, C₂–C₁₀ alkynyl, C₃–C₈ cycloalkyl,         C₅–C₈ cycloalkenyl, C₄–C₁₂ cycloalkylalkyl or C₆–C₁₀         cycloalkenylalkyl, each optionally substituted with 1 to 3         substituents independently selected at each occurrence from         C₁–C₆ alkyl, C₃–C₆ cycloalkyl, halo, C₁–C₄ haloalkyl, cyano,         OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵,         N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl,         heteroaryl and heterocyclyl; -   R⁴ is independently selected at each occurrence from: C₁–C₁₀ alkyl,     C₂–C₁₀ alkenyl, C₂–C₁₀ alkynyl, C₃–C₆ cycloalkyl, C₄–C₁₂     cycloalkylalkyl, NO₂, halo, CN, C₁–C₄ haloalkyl, NR⁶R⁷, NR⁸COR⁷,     NR⁸CO₂R⁷, COR⁷, OR⁷, CONR⁶R⁷, CO(NOR⁹)R⁷, CO₂R⁷, or S(O)_(n)R⁷,     where each such C₁–C₁₀ alkyl, C₂–C₁₀ alkenyl, C₂–C₁₀ alkynyl, C₃–C₆     cycloalkyl and C₄–C₁₂ cycloalkylalkyl are optionally substituted     with 1 to 3 substituents independently selected at each occurrence     from C₁–C₄ alkyl, NO₂, halo, CN, NR⁶R⁷, NR⁸COR⁷, NR⁸CO₂R⁷, COR⁷ OR⁷,     CONR⁶R⁷, CO₂R⁷, CO(NOR⁹)R⁷, or S(O)_(n)R⁷; -   R⁶ and R⁷, R^(6a) and R^(7a) are independently selected at each     occurrence from:     -   —H,     -   —C₁–C₁₀ alkyl, C₃–C₁₀ alkenyl, C₃–C₁₀ alkynyl, C₁–C₁₀ haloalkyl         with 1–10 halogens, C₂–C₈ alkoxyalkyl, C₃–C₆ cycloalkyl, C₄–C₁₂         cycloalkylalkyl, C₅–C₁₀ cycloalkenyl, or C₆–C₁₄         cycloalkenylalkyl, each optionally substituted with 1 to 3         substituents independently selected at each occurrence from         C₁–C₆ alkyl, C₃–C₆ cycloalkyl, halo, C₁–C₄ haloalkyl, cyano,         OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵,         N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl,         heteroaryl or heterocyclyl,     -   -aryl, aryl(C₁–C₄ alkyl), heteroaryl, heteroaryl(C₁–C₄ alkyl),         heterocyclyl or heterocyclyl(C₁–C₄ alkyl);         alternatively, NR⁶R⁷ and NR^(6a)R^(7a) are independently         piperidine, pyrrolidine, piperazine, N-methylpiperazine,         morpholine or thiomorpholine, each optionally substituted with         1–3 C₁–C₄ alkyl groups; -   R⁸ is independently selected at each occurrence from H or C₁–C₄     alkyl; -   R⁹ and R¹⁰ are independently selected at each occurrence from H,     C₁–C₄ alkyl, or C₃–C₆ cycloalkyl; -   R¹¹ is selected from H, C₁–C₄ alkyl, C₁–C₄ haloalkyl, or C₃–C₆     cycloalkyl; -   R¹² is C₁–C₄ alkyl or C₁–C₄ haloalkyl; -   R¹³ is selected from C₁–C₄ alkyl, C₁–C₄ haloalkyl, C₂–C₈     alkoxyalkyl, C₃–C₆ cycloalkyl, C₄–C₁₂ cycloalkylalkyl, aryl,     aryl(C₁–C₄ alkyl)-, heteroaryl or heteroaryl(C₁–C₄ alkyl)-; -   R¹⁴ is selected from C₁–C₁₀ alkyl, C₃–C₁₀ alkenyl, C₃–C₁₀ alkynyl,     C₃–C₈ cycloalkyl, or C₄–C₁₂ cycloalkylalkyl, each optionally     substituted with 1 to 3 substituents independently selected at each     occurrence from C₁–C₆ alkyl, C₃–C₆ cycloalkyl, halo, C₁–C₄     haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹⁵, COR¹⁵, CO₂R¹⁵, OC(O)R¹⁵,     NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹⁵, NR¹⁶R¹⁵, CONR¹⁶R¹⁵,     and C₁–C₆ alkylthio, C₁–C₆ alkylsulfinyl and C₁–C₆ alkylsulfonyl; -   R¹⁵ and R¹⁶ are independently selected at each occurrence from H,     C₁–C₆ alkyl, C₃–C₁₀ cycloalkyl, C₄–C₁₆ cycloalkylalkyl, except that     for S(O)_(n)R¹⁵, R¹⁵ cannot be H; -   aryl is phenyl or naphthyl, each optionally substituted with 1 to 5     substituents independently selected at each occurrence from C₁–C₆     alkyl, C₃–C₆ cycloalkyl, halo, C₁–C₄ haloalkyl, cyano, OR¹⁵, SH,     S(O)_(n)R¹⁵, COR¹⁵, CO₂R¹⁵, OC(O)R¹⁵, NR⁸COR¹⁵, N(COR¹⁵)₂,     NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹⁵, NR¹⁶R¹⁵, and CONR¹⁶R¹⁵; -   heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, pyranyl,     quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl,     pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl,     isoxazolyl, pyrazolyl, 2,3-dihydrobenzothienyl or     2,3-dihydrobenzofuranyl, each being optionally substituted with 1 to     5 substituents independently selected at each occurrence from C₁–C₆     alkyl, C₃–C₆ cycloalkyl, halo, C₁–C₄ haloalkyl, cyano, OR¹⁵, SH,     S(O)_(n)R¹⁵, —COR¹⁵, CO₂R¹⁵, OC(O)R¹⁵, NR⁸COR¹⁵, N(COR¹⁵)₂,     NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹⁵, NR¹⁶R¹⁵, and CONR¹⁶R¹⁵; -   heterocyclyl is saturated or partially saturated heteroaryl,     optionally substituted with 1 to 5 substituents independently     selected at each occurrence from C₁–C₆ alkyl, C₃–C₆ cycloalkyl,     halo, C₁–C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹⁵, COR¹⁵, CO₂R¹⁵,     OC(O)R¹⁵, NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹⁵, NR¹⁵R¹⁶, and     CONR¹⁶R¹⁵; -   n is independently at each occurrence 0, 1 or 2, -   with the provisos that:     -   (1) when A is N, Z is CR², R² is H, R³ is —OR⁷ or —OCOR¹³, and         R⁷ is H, then R¹ is not H, OH or SH;     -   (2) when A is N, Z is CR², R¹ is CH₃ or C₂H₅, R² is H, and R³ is         OH, H, CH₃, C₂H₅, C₆H₅, n-C₃H₇, i-C₃H₇, SH, SCH₃, NHC₄H₉, or         N(C₂H₅)₂, then Ar is not phenyl or m-CH₃-phenyl;     -   (3) when A is N, Z is CR², R² is H, and Ar is pyridyl,         pyrimidinyl or pyrazinyl, and R³ is NR^(6a)R^(7a), then R^(6a)         and R^(7a) are not H or alkyl;     -   (4) when A is N, Z is CR², and R² is SO₂NR⁶R⁷, then R³ is not OH         or SH;     -   (5) when A is CR and Z is CR², then R² is not —NR⁶SO₂R⁷ or         —SO₂NR⁶R⁷;     -   (6) when A is N, Z is CR² and R² is —NR⁶SO₂R⁷ or —SO₂NR⁶R⁷, then         R³ is not OH or SH;     -   (7) when A is N, Z is CR², R¹ is methyl or ethyl, R² is H, and         R³ is H, OH, CH₃, C₂H₅, C₆H₅, n-C₃H₇, iso-C₃H₇, SH, SCH₃,         NH(n-C₄H₉), or N(C₂H₅)₂, then Ar is not unsubstituted phenyl or         m-methylphenyl;     -   (8) when A is CR, Z is CR², R² is H, phenyl or alkyl, R³ is         NR⁸COR⁷ and Ar is phenyl or phenyl substituted with phenylthio,         then R⁷ is not aryl, aryl(C₁–C₄ alkyl), heteroaryl,         heteroaryl(C₁–C₄ alkyl), heterocyclyl or heterocycly(C₁–C₄         alkyl);     -   (9) when A is CR, Z is CR², R² is H or alkyl, Ar is phenyl, and         R³ is SR¹³ or NR^(6a)R^(7a), then R¹³ is not aryl or heteroaryl         and R^(6a) and R^(7a) are not H or aryl; or     -   (10) when A is CH, Z is CR², R¹ is OR¹¹, R² is H, R³ is OR⁷, and         R⁷ and R¹¹ are both H, then Ar is not phenyl, p-Br-phenyl,         p-Cl-phenyl, p-NHCOCH₃-phenyl, p-CH₃-phenyl, pyridyl or         naphthyl;     -   (11) when A is CH, Z is CR², R² is H, Ar is unsubstituted         phenyl, and R³ is CH₃, C₂H₅, CF₃ or C₆H₄F, then R₁, is not CF₃         or C₂F₅;     -   (12) when A is CR, R is H, Z is CR², R² is OH, and R¹ and R³ are         H, then Ar is not phenyl;     -   (13) when A is CR, R is H, Z is CR², R² is OH or NH₂, R¹ and R³         are CH₃, then Ar is not 4-phenyl-3-cyano-2-aminopyrid-2-yl.

Preferred compounds of the above invention are compounds of Formulae (1) and (2) and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof with the additional provisos that: (1) when A is N, R¹ is H, C₁–C₄ alkyl, halo, CN, C₁–C₁₂ hydroxyalkyl, C₁–C₄ alkoxyalkyl or SO₂(C₁–C₄ alkyl), R³ is NR^(6a)R^(7a) and R^(6a) is unsubstituted C₁–C₄ alkyl, then R^(7a) is not phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, furanyl, benzofuranyl, benzothiazolyl, indolyl or C₃–C₆ cycloalkyl; and (2) A is N, R¹ is H, C₁–C₄ alkyl, halo, CN, C₁–C₁₂ hydroxyalkyl, C₁–C₄ alkoxyalkyl or SO₂(C₁–C₄ alkyl), R³ is NR^(6a)R^(7a) and R^(7a) is unsubstituted C₁–C₄ alkyl, then R^(6a) is not phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, furanyl, benzofuranyl, benzothiazolyl, indolyl or C₃–C₆ cycloalkyl.

Preferred compounds of the above invention also include compounds of Formulae (1) and (2) and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, each optionally substituted with 1 to 4 R⁴ substituents.

Preferred compounds of the above invention also include compounds of Formulae (1) and (2) and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein A is N, Z is CR², Ar is 2,4-dichlorophenyl, 2,4-dimethylphenyl or 2,4,6-trimethylphenyl, R¹ and R² are CH₃, and R³ is NR^(6a)R^(7a).

More preferred compounds of the above invention are compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein A is N.

More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof.

More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl and each Ar is optionally substituted with 1 to 4 R⁴ substituents.

More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R³ is NR^(6a)R^(7a) or OR⁷.

More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to 4 R⁴ substituents, and R³ is NR^(6a)R^(7a) or OR⁷.

More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein Z is CR².

More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl and each Ar is optionally substituted with 1 to 4 R⁴ substituents.

More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R³ is NR^(6a)R^(7a) or OR⁷.

More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein

-   R^(6a) is independently selected from:     -   —H,     -   —C₁–C₁₀ alkyl, C₃–C₁₀ alkenyl, C₃–C₁₀ alkynyl, C₁–C₁₀ haloalkyl         with 1–10 halogens, C₂–C₈ alkoxyalkyl, C₃–C₆ cycloalkyl, C₄–C₁₂         cycloalkylalkyl, C₅–C₁₀ cycloalkenyl, or C₆–C₁₄         cycloalkenylalkyl, each optionally substituted with 1 to 3         substituents independently selected at each occurrence from         C₁–C₆ alkyl, C₃–C₆ cycloalkyl, halo, C₁–C₄ haloalkyl, cyano,         OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵,         N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl,         heteroaryl or heterocyclyl, -   -aryl, aryl(C₁–C₄ alkyl), heteroaryl, heteroaryl(C₁–C₄ alkyl),     heterocyclyl or heterocyclyl(C₁–C₄ alkyl); and -   R^(7a) is independently selected at each occurrence from:     -   —H,     -   —C₅–C₁₀ alkyl, C₃–C₁₀ alkenyl, C₃–C₁₀ alkynyl, C₁–C₁₀ haloalkyl         with 1–10 halogens, C₂–C₈ alkoxyalkyl, C₃–C₆ cycloalkyl, C₄–C₁₂         cycloalkylalkyl, C₅–C₁₀ cycloalkenyl, or C₆–C₁₄         cycloalkenylalkyl, each optionally substituted with 1 to 3         substituents independently selected at each occurrence from         C₁–C₆ alkyl, C₃–C₆ cycloalkyl, halo, C₁–C₄ haloalkyl, cyano,         OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵,         N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl,         heteroaryl or heterocyclyl,     -   -aryl, aryl(C₁–C₄ alkyl), heteroaryl, heteroaryl(C₁–C₄ alkyl),         heterocyclyl or heterocyclyl(C₁–C₄ alkyl);         alternatively, NR⁶R⁷ and NR^(6a)R^(7a) are independently         piperidine, pyrrolidine, piperazine, N-methylpiperazine,         morpholine or thiomorpholine, each optionally substituted with         1–3 C₁–C₄ alkyl groups.

More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R^(6a) and R^(7a) are identical and are selected from:

-   -   —C₁–C₄ alkyl or C₃–C₆ cycloalkyl, each optionally substituted         with 1 to 3 substituents independently selected at each         occurrence from C₁–C₆ alkyl, C₃–C₆ cycloalkyl, halo, C₁–C₄         haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹³, —COR¹⁵, CO₂R¹⁵,         OC(O)R¹³, NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵,         CONR¹⁶R¹⁵, aryl, heteroaryl or heterocyclyl, and -aryl or         heteroaryl.

More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein

-   R^(6a) is selected from:     -   —H,     -   —C₁–C₁₀ alkyl, C₃–C₁₀ alkenyl, C₃–C₁₀ alkynyl, C₁–C₁₀ haloalkyl         with 1–10 halogens, C₂–C₈ alkoxyalkyl, C₃–C₆ cycloalkyl, C₄–C₁₂         cycloalkylalkyl, C₅–C₁₀ cycloalkenyl, or C₆–C₁₄         cycloalkenylalkyl, each optionally substituted with 1 to 3         substituents independently selected at each occurrence from         C₁–C₆ alkyl, C₃–C₆ cycloalkyl, halo, C₁–C₄ haloalkyl, cyano,         OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵,         N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl,         heteroaryl or heterocyclyl,     -   -aryl, aryl(C₁–C₄ alkyl), heteroaryl, heteroaryl(C₁–C₄ alkyl),         heterocyclyl or heterocyclyl(C₁–C₄ alkyl); -   R^(7a) is selected from:     -   —C₁–C₄ alkyl and each such C₁–C₄ alkyl is substituted with 1–3         substituents independently selected at each occurrence from         C₁–C₆ alkyl, C₃–C₆ cycloalkyl, halo, C₁–C₄ haloalkyl, cyano,         OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵,         N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl,         heteroaryl or heterocyclyl.

More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein one of R^(6a) and R^(7a) is selected from:

-   -   —C₃–C₆ cycloalkyl, each such C₃–C₆ cycloalkyl optionally         substituted with 1–3 substituents independently selected at each         occurrence from C₁–C₆ alkyl, C₃–C₆ cycloalkyl, halo, C₁–C₄         haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵,         OC(O)R¹³, NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵,         CONR¹⁶R¹⁵, aryl, heteroaryl or heterocyclyl,     -   -aryl,     -   -heteroaryl or     -   -heterocyclyl,         and the other of R^(6a) and R^(7a) is unsubstituted C₁–C₄ alkyl.

More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R^(6a) and R^(7a) are independently H or C₁–C₁₀ alkyl, each such C₁–C₁₀ alkyl optionally substituted with 1 to 3 substituents independently selected at each occurrence from C₁–C₆ alkyl, C₃–C₆ cycloalkyl, halo, C₁–C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵, N(COR¹⁵)₂, R⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl, heteroaryl or heterocyclyl.

More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to 4 R⁴ substituents, and R³ is NR^(6a)R^(7a) or OR⁷.

More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein

-   R^(6a) is independently selected from:     -   —H,     -   —C₁–C₁₀ alkyl, C₃–C₁₀ alkenyl, C₃–C₁₀ alkynyl, C₁–C₁₀ haloalkyl         with 1–10 halogens, C₂–C₈ alkoxyalkyl, C₃–C₆ cycloalkyl, C₄–C₁₂         cycloalkylalkyl, C₅–C₁₀ cycloalkenyl, or C₆–C₁₄         cycloalkenylalkyl, each optionally substituted with 1 to 3         substituents independently selected at each occurrence from         C₁–C₆ alkyl, C₃–C₆ cycloalkyl, halo, C₁–C₄ haloalkyl, cyano,         OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵,         N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl,         heteroaryl or heterocyclyl,     -   -aryl, aryl(C₁–C₄ alkyl), heteroaryl, heteroaryl(C₁–C₄ alkyl),         heterocyclyl or heterocyclyl(C₁–C₄ alkyl); -   R^(7a) is independently selected at each occurrence from:     -   —H,     -   —C₅–C₁₀ alkyl, C₃–C₁₀ alkenyl, C₃–C₁₀ alkynyl, C₁–C₁₀ haloalkyl         with 1–10 halogens, C₂–C₈ alkoxyalkyl, C₃–C₆ cycloalkyl, C₄–C₁₂         cycloalkylalkyl, C₅–C₁₀ cycloalkenyl, or C₆–C₁₄         cycloalkenylalkyl, each optionally substituted with 1 to 3         substituents independently selected at each occurrence from         C₁–C₆ alkyl, C₃–C₆ cycloalkyl, halo, C₁–C₄ haloalkyl, cyano,         OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵,         N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl,         heteroaryl or heterocyclyl,     -   -aryl, aryl(C₁–C₄ alkyl), heteroaryl, heteroaryl(C₁–C₄ alkyl),         heterocyclyl or heterocyclyl(C₁–C₄ alkyl);         alternatively, NR⁶R⁷ and NR^(6a)R^(7a) are independently         piperidine, pyrrolidine, piperazine, N-methylpiperazine,         morpholine or thiomorpholine, each optionally substituted with         1–3 C₁–C₄ alkyl groups.

More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R^(6a) and R^(7a) are identical and are selected from:

-   -   —C₁–C₄ alkyl or C₃–C₆ cycloalkyl, each optionally substituted         with 1 to 3 substituents independently selected at each         occurrence from C₁–C₆ alkyl, C₃–C₆ cycloalkyl, halo, C₁–C₄         haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹³, —COR¹⁵, CO₂R¹⁵,         OC(O)R¹³, NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵,         CONR¹⁶R¹⁵, aryl, heteroaryl or heterocyclyl, and -aryl or         heteroaryl.

More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R^(6a) and R^(7a) are identical and are

-   -   —C₁–C₄ alkyl, each such C₁–C₄ alkyl optionally substituted with         1 to 3 substituents independently selected at each occurrence         from C₁–C₆ alkyl, C₃–C₆ cycloalkyl, halo, C₁–C₄ haloalkyl,         cyano, OR¹⁵, SH, S(O)_(n)R¹³—COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵,         N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl,         heteroaryl or heterocyclyl.

More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R^(6a) is selected from:

-   -   —H,     -   —C₁–C₁₀ alkyl, C₃–C₁₀ alkenyl, C₃–C₁₀ alkynyl, C₁–C₁₀ haloalkyl         with 1–10 halogens, C₂–C₈ alkoxyalkyl, C₃–C₆ cycloalkyl, C₄–C₁₂         cycloalkylalkyl, C₅–C₁₀ cycloalkenyl, or C₆–C₁₄         cycloalkenylalkyl, each optionally substituted with 1 to 3         substituents independently selected at each occurrence from         C₁–C₆ alkyl, C₃–C₆ cycloalkyl, halo, C₁–C₄ haloalkyl, cyano,         OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵,         N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl,         heteroaryl or heterocyclyl,     -   -aryl, aryl(C₁–C₄ alkyl), heteroaryl, heteroaryl(C₁–C₄ alkyl),         heterocyclyl or heterocyclyl(C₁–C₄ alkyl);

-   R^(7a) is:     -   —C₁–C₄ alkyl and each such C₁–C₄ alkyl is substituted with 1–3         substituents independently selected at each occurrence from         C₁–C₆ alkyl, C₃–C₆ cycloalkyl, halo, C₁–C₄ haloalkyl, cyano,         OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵,         N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl,         heteroaryl or heterocyclyl.

More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein one of R^(6a) and R^(7a) is selected from:

-   -   —C₃–C₆ cycloalkyl, each such C₃–C₆ cycloalkyl optionally         substituted with 1–3 substituents independently selected at each         occurrence from C₁–C₆ alkyl, C₃–C₆ cycloalkyl, halo, C₁–C₄         haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵,         OC(O)R¹³, NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵,         CONR¹⁶R¹⁵, aryl, heteroaryl or heterocyclyl,     -   -aryl,     -   -heteroaryl or     -   -heterocyclyl,         and the other of R^(6a) and R^(7a) is unsubstituted C₁–C₄ alkyl.

More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R^(6a) and R^(7a) are independently H or C₁–C₁₀ alkyl, each such C₁–C₁₀ alkyl optionally substituted with 1 to 3 substituents independently selected at each occurrence from C₁–C₆ alkyl, C₃–C₆ cycloalkyl, halo, C₁–C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵, N(COR¹⁵)₂, R⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl, heteroaryl or heterocyclyl.

More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein

-   -   —Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar         is optionally substituted with 1 to 4 R⁴ substituents,     -   —R³ is NR^(6a)R^(7a) or OR⁷ and     -   —R¹ and R² are independently selected from H, C₁–C₄ alkyl, C₃–C₆         cycloalkyl, C₄–C₁₀ cycloalkylalkyl.

More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein

-   R^(6a) is independently selected from:     -   —H,     -   —C₁–C₁₀ alkyl, C₃–C₁₀ alkenyl, C₃–C₁₀ alkynyl, C₁–C₁₀ haloalkyl         with 1–10 halogens, C₂–C₈ alkoxyalkyl, C₃–C₆ cycloalkyl, C₄–C₁₂         cycloalkylalkyl, C₅–C₁₀ cycloalkenyl, or C₆–C₁₄         cycloalkenylalkyl, each optionally substituted with 1 to 3         substituents independently selected at each occurrence from         C₁–C₆ alkyl, C₃–C₆ cycloalkyl, halo, C₁–C₄ haloalkyl, cyano,         OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵,         N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl,         heteroaryl or heterocyclyl,     -   -aryl, aryl(C₁–C₄ alkyl), heteroaryl, heteroaryl(C₁–C₄ alkyl),         heterocyclyl or heterocyclyl(C₁–C₄ alkyl); -   R^(7a) is independently selected at each occurrence from:     -   —H,     -   —C₅–C₁₀ alkyl, C₃–C₁₀ alkenyl, C₃–C₁₀ alkynyl, C₁–C₁₀ haloalkyl         with 1–10 halogens, C₂–C₈ alkoxyalkyl, C₃–C₆ cycloalkyl, C₄–C₁₂         cycloalkylalkyl, C₅–C₁₀ cycloalkenyl, or C₆–C₁₄         cycloalkenylalkyl, each optionally substituted with 1 to 3         substituents independently selected at each occurrence from         C₁–C₆ alkyl, C₃–C₆ cycloalkyl, halo, C₁–C₄ haloalkyl, cyano,         OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵,         N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl,         heteroaryl or heterocyclyl,     -   -aryl, aryl(C₁–C₄ alkyl), heteroaryl, heteroaryl(C₁–C₄ alkyl),         heterocyclyl or heterocyclyl(C₁–C₄ alkyl);         alternatively, NR⁶R⁷ and NR^(6a)R^(7a) are independently         piperidine, pyrrolidine, piperazine, N-methylpiperazine,         morpholine or thiomorpholine, each optionally substituted with         1–3 C₁–C₄ alkyl groups.

More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R^(6a) and R^(7a) are identical and are selected from:

-   -   —C₁–C₄ alkyl or C₃–C₆ cycloalkyl, each optionally substituted         with 1 to 3 substituents independently selected at each         occurrence from C₁–C₆ alkyl, C₃–C₆ cycloalkyl, halo, C₁–C₄         haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹³, —COR¹⁵, CO₂R¹⁵,         OC(O)R¹³, NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵,         CONR¹⁶R¹⁵, aryl, heteroaryl or heterocyclyl, and -aryl or         heteroaryl.

More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R^(6a) and R^(7a) are identical and are

-   -   —C₁–C₄ alkyl, each such C₁–C₄ alkyl optionally substituted with         1 to 3 substituents independently selected at each occurrence         from C₁–C₆ alkyl, C₃–C₆ cycloalkyl, halo, C₁–C₄ haloalkyl,         cyano, OR¹⁵, SH, S(O)_(n)R¹³, —COR¹⁵, CO₂R¹⁵, OC(O)R¹³,         NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵,         CONR¹⁶R¹⁵, aryl, heteroaryl or heterocyclyl.

More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein

-   R^(6a) is selected from:     -   —H,     -   —C₁–C₁₀ alkyl, C₃–C₁₀ alkenyl, C₃–C₁₀ alkynyl, C₁–C₁₀ haloalkyl         with 1–10 halogens, C₂–C₈ alkoxyalkyl, C₃–C₆ cycloalkyl, C₄–C₁₂         cycloalkylalkyl, C₅–C₁₀ cycloalkenyl, or C₆–C₁₄         cycloalkenylalkyl, each optionally substituted with 1 to 3         substituents independently selected at each occurrence from         C₁–C₆ alkyl, C₃–C₆ cycloalkyl, halo, C₁–C₄ haloalkyl, cyano,         OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵,         N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl,         heteroaryl or heterocyclyl,     -   -aryl, aryl(C₁–C₄ alkyl), heteroaryl, heteroaryl(C₁–C₄ alkyl),         heterocyclyl or heterocyclyl(C₁–C₄ alkyl); -   R^(7a) is:     -   —C₁–C₄ alkyl and each such C₁–C₄ alkyl is substituted with 1–3         substituents independently selected at each occurrence from         C₁–C₆ alkyl, C₃–C₆ cycloalkyl, halo, C₁–C₄ haloalkyl, cyano,         OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵,         N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl,         heteroaryl or heterocyclyl.

More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein one of R^(6a) and R^(7a) is selected from:

-   -   —C₃–C₆ cycloalkyl, each such C₃–C₆ cycloalkyl optionally         substituted with 1–3 substituents independently selected at each         occurrence from C₁–C₆ alkyl, C₃–C₆ cycloalkyl, halo, C₁–C₄         haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵,         OC(O)R¹³, NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵,         CONR¹⁶R¹⁵, aryl, heteroaryl or heterocyclyl,     -   -aryl,     -   -heteroaryl or     -   -heterocyclyl,         and the other of R^(6a) and R^(7a) is unsubstituted C₁–C₄ alkyl.

More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R^(6a) and R^(7a) are independently H or C₁–C₁₀ alkyl, each such C₁–C₁₀ alkyl optionally substituted with 1 to 3 substituents independently selected at each occurrence from C₁–C₆ alkyl, C₃–C₆ cycloalkyl, halo, C₁–C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵, N(COR¹⁵)₂, R⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl, heteroaryl or heterocyclyl.

Specifically preferred compounds of the above invention are compounds of Formula (50)

and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof, selected from the group consisting of:

-   a compound of Formula (50) wherein R³ is —NHCH(n-Pr)₂, R^(4a) is Cl,     R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —N(Et)(n-Bu), R^(4a) is Cl,     R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is -(n-Pr)(CH₂cPr), R^(4a) is     Cl, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —N(CH₂CH₂OMe)₂, R^(4a) is     Cl, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —NHCH(Et)(n-Bu), R^(4a) is     Cl, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —NHCH(Et)(CH₂OMe), R^(4a)     is Cl, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —NHCH(CH₂OMe)₂, R^(4a) is     Cl, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —N(Et)₂, R^(4a) is C¹,     R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —NHCH(CH₂OEt)₂, R^(4a) is     Cl, R^(4b) is H, R^(4c) is C¹, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —NHCH(Et)₂, R^(4a) is Cl,     R^(4b) is H, R^(4c) is C¹, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —N(Me)(Ph), R^(4a) is C¹,     R^(4b) is H, R^(4c) is C¹, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —N(n-Pr)₂, R^(4a) is C¹,     R^(4b) is H, R^(4c) is C¹, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —NHCH(Et)(n-Pr), R^(4a) is     C¹, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —NHCH(CH₂OMe)₂, R^(4a) is     Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is Me; -   a compound of Formula (50) wherein R³ is —NHCH(CH₂OMe)₂, R^(4a) is     Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —N(CH₂CH₂OMe)₂, R^(4a) is     Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —NHCH(Et)(CH₂OMe), R^(4a)     is Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —NHCH(Et)₂, R^(4a) is Me,     R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —OEt, R^(4a) is C¹, R^(4b)     is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —N(Et)₂, R^(4a) is Me,     R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —N(CH₂CN)₂, R^(4a) is Me,     R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —NHCH(Me)(CH₂OMe), R^(4a)     is Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —OCH(Et)(CH₂OMe), R^(4a) is     Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —N(n-Pr)(CH₂c-Pr), R^(4a)     is Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —NHCH(Me)(CH₂N(Me)₂),     R^(4a) is Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is     H; -   a compound of Formula (50) wherein R³ is —N(cPr)(CH₂CH₂CN), R^(4a)     is Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —N(n-Pr)(CH₂CH₂CN), R^(4a)     is Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —N(n-Bu)(CH₂CN), R^(4a) is     Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is NHCH(Et)(CH₂OMe), R^(4a) is     Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is Me; -   a compound of Formula (50) wherein R³ is —NHCH(Et)₂, R^(4a) is Me,     R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is Me; -   a compound of Formula (50) wherein R³ is —N(CH₂CH₂OMe)₂, R^(4a) is     Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is Me; -   a compound of Formula (50) wherein R³ is —NHCH(CH₂OMe)₂, R^(4a) is     Br, R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —NHCH(Et)(CH₂OMe), R^(4a)     is Br, R^(4b) is H R^(4c) is OMe, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —N(Et)₂, R^(4a) is Me,     R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is Me; -   a compound of Formula (50) wherein R³ is —NHCH(CH₂OEt)₂, R^(4a) is     Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is Me; -   a compound of Formula (50) wherein R³ is —NHCH(CH₂CH₂OMe)(CH₂OMe)₂,     R^(4a) is Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is     Me; -   a compound of Formula (50) wherein R³ is morpholino, R^(4a) is Me,     R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —N(CH₂CH₂OMe)₂, R^(4a) is     Br, R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R^(4c) is H; -   a compound of Formula (50) wherein R³ is —NHCH(Et)₂, R^(4a) is Br,     R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —N(Et)₂, R^(4a) is Br,     R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —NH(c-Pr), R^(4a) is Me,     R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is NHCH(CH₂OMe)₂, R^(4a) is     CN, R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —N(c-Pr)(CH₂CH₂CN), R^(4a)     is Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is Me; -   a compound of Formula (50) wherein R³ is —NCH(CH₂OMe)₂, R^(4a) is     Me, R^(4b) is H, R^(4c) is Br, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —NHCH(CH₂OMe)(CH₂CH₂OMe),     R^(4a) is Me, R^(4b) is H, R^(4c) is Br, R^(4d) is H and R^(4e) is     H; -   a compound of Formula (50) wherein R³ is —NHCH(CH₂OMe)₂, R^(4a) is     Me, R^(4b) is H, R^(4c) is OMe, R^(4d) is Me and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —N(CH₂CH₂OMe)₂, R^(4a) is     Me, R^(4b) is H, R^(4c) is OMe, R^(4d) is Me and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —NHCH(Et)₂, R^(4a) is Me,     R^(4b) is H, R^(4c) is OMe, R^(4d) is Me and R^(4e) is H; -   a compound of Formula (50) wherein a compound of Formula (50)     wherein R³ is —N(Et)₂, R^(4a) is Me, R^(4b) is H, R^(4c) is OMe,     R^(4d) is Me and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —NHCH(CH₂OMe)₂, R^(4a) is     Cl, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —NHCH(Et)(CH₂OMe), R^(4a)     is C¹, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —N(CH₂CH₂OMe)₂, R^(4a) is     C¹, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —NHCH(CH₂OMe)(CH₂CH₂OMe),     R^(4a) is C¹, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is     H; -   a compound of Formula (50) wherein R³ is —N(c-Pr)(CH₂CH₂CN), R^(4a)     is Me, R^(4b) is H, R^(4c) is OMe, R^(4d) is Me and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —N(cPr)(CH₂CH₂CN), R^(4a)     is C¹, R^(4b) is H, R^(4c) is C¹, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is     (S)—NHCH(CH₂OMe)(CH₂CH₂OMe), R^(4a) is Cl, R^(4b) is H, R^(4c) is     C¹, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —NHCH(CH₂OMe)(CH₂CH₂OMe),     R^(4a) is Cl, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is     H; -   a compound of Formula (50) wherein R³ is —NHCH(Et)₂, R^(4a) is Me,     R^(4b) is H, R^(4c) is Br, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —N(CH₂CH₂OMe)₂, R^(4a) is     Me, R^(4b) is H, R^(4c) is Br, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —NH(CH₂OMe)(CH₂-iPr),     R^(4a) is Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is     H; -   a compound of Formula (50) wherein R³ is —N(CH₂CH₂OMe)₂, R^(4a) is     Me, R^(4b) is H, R^(4c) is H, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —N(CH₂CH₂OMe)₂, R^(4a) is     Me, R^(4b) is H, R^(4c) is NMe₂, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —NHCH(CH₂OMe)(n-Pr), R^(4a)     is Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —NHCH(CH₂OEt)(Et), R^(4a)     is Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —NHCH(CH₂OMe)(CH₂CH₂OMe),     R^(4a) is Me, R^(4b) is H, R^(4c) is NMe2, R^(4d) is H and R^(4e) is     H; -   a compound of Formula (50) wherein R³ is —N(Et)₂, R^(4a) is Me,     R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —NHCH(Et)₂, R^(4a) is Me,     R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —N(CH₂CH₂OMe)₂, R^(4a) is     Me, R^(4b) is H, R^(4c) is C¹, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —NHCH(CH₂OMe)₂, R^(4a) is     Me, R^(4b) is H, R^(4c) is C¹, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —N(Et)₂, R^(4a) is Me,     R^(4b) is H, R^(4c) is Br, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —N(Et)₂, R^(4a) is Cl,     R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —NHCH(Et)₂, R^(4a) is C¹,     R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —NHCH(Et)₂, R^(4a) is Me,     R^(4b) is H, R^(4c) is NMe2, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is     (S)—NHCH(CH₂OMe)(CH₂CH₂OMe), R^(4a) is Me, R^(4b) is H, R^(4c) is     Me, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —NHCH(CH₂OMe)(CH₂CH₂OMe),     R^(4a) is Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is     H; -   a compound of Formula (50) wherein R³ is     (S)—NHCH(CH₂OMe)(CH₂CH₂OMe), R^(4a) is Me, R^(4b) is H, R^(4c) is     Cl, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —NHCH(CH₂OMe)(CH₂CH₂OMe),     R^(4a) is Me, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is     H; -   a compound of Formula (50) wherein R³ is —N(c-Pr)(CH₂CH₂CN), R^(4a)     is Me, R^(4b) is H, R^(4c) is C¹, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —NH(Et)(CH₂CN), R^(4a) is     Me, R^(4b) is H, R^(4c) is C¹, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —N(Et)₂, R^(4a) is Me,     R^(4b) is Me, R^(4c) is OMe, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —N(CH₂CH₂OMe)(CH₂CH₂OH),     R^(4a) is Cl, R^(4b) is H, R^(4c) is C¹, R^(4d) is H and R^(4e) is     H; -   a compound of Formula (50) wherein R³ is —N(CH₂CH₂OMe)₂, R^(4a) is     Me, R^(4b) is Me, R^(4c) is OMe, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —NHCH(Et)₂, R^(4a) is Me,     R^(4b) is Me, R^(4c) is OMe, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —N(CH₂c-Pr) (n-Pr), R^(4a)     is Me, R^(4b) is H, R^(4c) is C¹, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —N(c-Pr) (CH₂CH₂CN), R^(4a)     is Me, R^(4b) is Me, R^(4c) is OMe, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —NHCH (Et)₂, R^(4a) is C¹,     R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —N(Et)₂, R^(4a) is Cl,     R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —N(CH₂CH₂OMe)₂, R^(4a) is     C¹, R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —NHCH(Et)(CH₂OMe), R^(4a)     is C¹, R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —N(Et)₂, R^(4a) is Cl,     R^(4b) is H, R^(4c) is CN, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —N(c-Pr)(CH₂CH₂CN), R^(4a)     is C¹, R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H; -   a compound of Formula (50) wherein R³ is —NHCH(CH₂OH)₂, R^(4a) is     C¹, R^(4b) is H, R^(4c) is C¹, R^(4d) is H and R^(4e) is H; and -   a compound of Formula (50) wherein R³ is N(CH₂CH₂OMe)₂, R^(4a) is     Me, R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H.

More specifically preferred is 4-(bis-(2-methoxyethyl)amino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)-[1,5-a]-pyrazolo-1,3,5-triazine and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof.

More specifically preferred is 4(bis-(2-methoxyethyl)amino)-2,7-dimethyl-8-(2,5-dimethyl-4-methoxyphenyl)-[1,5-a]-pyrazolo-1,3,5-triazine and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof.

More preferred are compounds of the above invention are compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein A is CR.

More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof.

More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl and each Ar is optionally substituted with 1 to 4 R⁴ substituents.

More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R³ is NR^(6a)R^(7a) or OR⁷.

More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to 4 R⁴ substituents, and R³ is NR^(6a)R^(7a) or OR⁷.

More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein Z is CR².

More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl and each Ar is optionally substituted with 1 to 4 R⁴ substituents.

More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R³ is NR^(6a)R^(7a) or OR⁷.

More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to 4 R⁴ substituents, and R³ is NR^(6a)R^(7a) or OR⁷.

More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R^(6a) and R^(7a) are independently H or C₁–C₁₀ alkyl, and each such C₁–C₁₀ alkyl is optionally substituted with 1 to 3 substituents independently selected at each occurrence from C₁–C₆ alkyl, C₃–C₆ cycloalkyl, halo, C₁–C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵, N(COR¹⁵)₂, R⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl, heteroaryl or heterocyclyl.

More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein

-   -   —Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar         is optionally substituted with 1 to 4 R⁴ substituents,     -   —R³ is NR^(6a)R^(7a) or OR⁷ and     -   —R¹ and R² are independently selected from H, C₁–C₄ alkyl, C₃–C₆         cycloalkyl, C₄–C₁₀ cycloalkylalkyl.

More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R^(6a) and R^(7a) are independently H or C₁–C₁₀ alkyl, and each such C₁–C₁₀ alkyl is optionally substituted with 1 to 3 substituents independently selected at each occurrence from C₁–C₆ alkyl, C₃–C₆ cycloalkyl, halo, C₁–C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵, N(COR¹⁵)₂, R⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl, heteroaryl or heterocyclyl.

Specifically preferred compounds of the above invention are compounds of Formula (51)

and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof selected from the group consisting of:

-   a compound of Formula (51) wherein R³ is —NHCH(n-Pr)₂, R^(4a) is Me,     R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H; -   a compound of Formula (51) wherein R³ is —NHCH(CH₂OMe)₂, R^(4a) is     Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H; -   a compound of Formula (51) wherein R³ is N(CH₂CH₂OMe)₂, R^(4a) is     Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H; -   a compound of Formula (51) wherein R³ is —N(c-Pr)(CH₂CH₂CN), R^(4a)     is Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H; -   a compound of Formula (51) wherein R³ is —N(CH₂CH₂OMe)₂, R^(4a) is     C¹, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H; -   a compound of Formula (51) wherein R³ is —NHCH(CH₂OMe)₂, R^(4a) is     Cl, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H; -   a compound of Formula (51) wherein R³ is —NHCH(Et)₂, R^(4a) is Cl,     R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H; -   a compound of Formula (51) wherein R³ is —N(Et)₂, R^(4a) is Me,     R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H; -   a compound of Formula (51) wherein R³ is —N(n-Pr) (CH₂CH₂CN), R^(4a)     is Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H; -   a compound of Formula (51) wherein R³ is —N(n-Bu)(CH₂CH₂CN), R^(4a)     is Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H; -   a compound of Formula (51) wherein R³ is —NHCH(n-Pr)(CH₂OMe), R^(4a)     is Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H; -   a compound of Formula (51) wherein R³ is —NHCH(Et)₂, R^(4a) is Me,     R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H; -   a compound of Formula (51) wherein R³ is —NHCH(CH₂OMe)₂, R^(4a) is     Me, R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H; -   a compound of Formula (51) wherein R³ is (S)—NH(CH₂CH₂OMe)CH₂OMe,     R^(4a) is Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is     H; -   a compound of Formula (51) wherein R³ is —NH(CH₂CH₂OMe)CH₂OMe,     R^(4a) is Me, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is     H; -   a compound of Formula (51) wherein R³ is —N(CH₂CH₂OMe)₂, R^(4a) is     Me, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H; -   a compound of Formula (51) wherein R³ is —NH(Et), R^(4a) is Me,     R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H; -   a compound of Formula (51) wherein R³ is —NHCH(n-Pr)₂, R^(4a) is Me,     R^(4b) is H, R^(4c) is C¹, R^(4d) is H and R^(4e) is H; -   a compound of Formula (51) wherein R³ is —NHCH(CH₂OMe)₂, R^(4a) is     Me, R^(4b) is H, R^(4c) is C¹, R^(4d) is H and R^(4e) is H; -   a compound of Formula (51) wherein R³ is (S)—NH(CH₂CH₂OMe)CH₂OMe,     R^(4a) is Me, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is     H; -   a compound of Formula (51) wherein R³ is —NH(CH₂CH₂OMe)CH₂OMe,     R^(4a) is Me, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is     H; -   a compound of Formula (51) wherein R³ is —N(n-Pr)(CH₂CH₂CN), R^(4a)     is Me, R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H; -   a compound of Formula (51) wherein R³ is —N(Et)₂, R^(4a) is Me,     R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H; -   a compound of Formula (51) wherein R³ is (S)—NH(CH₂CH₂OMe)CH₂OMe,     R^(4a) is Cl, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is     H; -   a compound of Formula (51) wherein R³ is —NH(CH₂CH₂OMe)CH₂OMe,     R^(4a) is C¹, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is     H; -   a compound of Formula (51) wherein R³ is —N(Et)₂, R^(4a) is Cl,     R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H; -   a compound of Formula (51) wherein R³ is —N(c-Pr)(CH₂CH₂CN), R^(4a)     is Me, R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H; -   a compound of Formula (51) wherein R³ is —N(c-Pr)(CH₂CH₂CN), R^(4a)     is C¹, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H; -   a compound of Formula (51) wherein R³ is —NHCH (n-Pr)(CH₂OMe),     R^(4a) is Me, R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is     H; -   a compound of Formula (51) wherein R³ is —NHCH (n-Pr)(CH₂OMe),     R^(4a) is C¹, R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is     H; -   a compound of Formula (51) wherein R³ is —NHCH(Et)₂, R^(4a) is Br,     R^(4b) is H, R^(4c) is OMe, R^(4d) is OMe and R^(4e) is H; -   a compound of Formula (51) wherein R³ is —NHCH(Et)₂, R^(4a) is Br,     R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H; -   a compound of Formula (51) wherein R³ is —N(CH₂CH₂OMe)₂, R^(4a) is     Br, R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H; -   a compound of Formula (51) wherein R³ is —NHCH(CH₂OMe)₂, R^(4a) is     Br, R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H; -   a compound of Formula (51) wherein R³ is —N(Et)₂, R^(4a) is Me,     R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H; -   a compound of Formula (51) wherein R³ is —N(Et)₂, R^(4a) is Cl,     R^(4b) is H, R^(4c) is OMe, R^(4d) is OMe and R^(4e) is H; -   a compound of Formula (51) wherein R³ is —NHCH(Et)₂, R^(4a) is Cl,     R^(4b) is H, R^(4c) is OMe, R^(4d) is OMe and R^(4e) is H; -   a compound of Formula (51) wherein R³ is —N(CH₂CH₂OMe)₂, R^(4a) is     C¹, R^(4b) is H, R^(4c) is C¹, R^(4d) is H and R^(4e) is H; -   a compound of Formula (51) wherein R³ is —NHCH(CH₂OMe)₂, R^(4a) is     C¹, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H; -   a compound of Formula (51) wherein R³ is —N(Pr)(CH₂CH₂CN), R^(4a) is     C¹, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H; -   a compound of Formula (51) wherein R³ is —N(Bu)(Et), R^(4a) is C¹,     R^(4b) is H, R^(4c) is C¹, R^(4d) is H and R^(4e) is H; -   a compound of Formula (51) wherein R³ is —NHCH(Et)CH₂OMe, R^(4a) is     C¹, R^(4b) is H, R^(4c) is Cl, R^(4d) is H and R^(4e) is H; -   a compound of Formula (51) wherein R³ is —NHCH(Et)₂, R^(4a) is C¹,     R^(4b) is H, R^(4c) is C¹, R^(4d) is H and R^(4e) is H; -   a compound of Formula (51) wherein R³ is —NHCH(Et)₂, R^(4a) is Me,     R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H; -   a compound of Formula (51) wherein R³ is —NHCH(Et)₂, R^(4a) is C¹,     R^(4b) is H, R^(4c) is Me, R^(4d) is H and R^(4e) is H; -   a compound of Formula (51) wherein R³ is —NHCH(Et)₂, R^(4a) is Me,     R^(4b) is H, R^(4c) is C¹, R^(4d) is H and R^(4e) is H; -   a compound of Formula (51) wherein R³ is —NEt₂, R^(4a) is Me, R^(4b)     is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H; and -   a compound of Formula (51) wherein R³ is —N(Pr)(CH₂CH₂CN), R^(4a) is     Me, R^(4b) is H, R^(4c) is OMe, R^(4d) is H and R^(4e) is H.

More specifically preferred is 7-(3-pentylamino)-2,5-dimethyl-3-(2-methyl-4-methoxyphenyl)-[1,5-a]-pyrazolopyrimidine and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof.

More specifically preferred is 7-(Diethylamino)-2,5-dimethyl-3-(2-methyl-4-methoxyphenyl-[1,5-a]-pyrazolopyrimidine and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof.

More specifically preferred is 7-(N-(3-cyanopropyl)-N-propylamino)-2,5-dimethyl-3-(2,4-dimethylphenyl)-[1,5-a]-pyrazolopyrimidine and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof.

The present invention also provides pharmaceutical compositions comprising compounds of Formulae (1) and (2) and a pharmaceutically acceptable carrier.

The present invention still further comprises a method of treating affective disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other feeding disorder, drug addiction, drug or alcohol withdrawal symptoms, inflammatory diseases, cardiovascular or heart-related diseases, fertility problems, human immunodeficiency virus infections, hemorrhagic stress, obesity, infertility, head and spinal cord traumas, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis, hypoglycemia or a disorder the treatment of which can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, in mammals comprising administering to the mammal a therapeutically effective amount of a compound of Formulae (1) or (2):

and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt forms thereof, wherein:

-   Z is N or CR²; -   Ar is selected from phenyl, naphthyl, pyridyl, pyrimidinyl,     triazinyl, furanyl, thienyl, benzothienyl, benzofuranyl,     2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, indanyl,     1,2-benzopyranyl, 3,4-dihydro-1,2-benzopyranyl, tetralinyl, each Ar     optionally substituted with 1 to 5 R⁴ groups and each Ar is attached     to an unsaturated carbon atom; -   R¹ is independently selected at each occurrence from H, C₁–C₄ alkyl,     C₂–C₄ alkenyl, C₂–C₄ alkynyl, halo, CN, C₁–C₄ haloalkyl, C₁–C₁₂     hydroxyalkyl, C₂–C₁₂ alkoxyalkyl, C₂–C₁₀ cyanoalkyl, C₃–C₆     cycloalkyl, C₄–C₁₀ cycloalkylalkyl, NR⁹R¹⁰, C₁–C₄ alkyl-NR⁹R¹⁰,     NR⁹COR¹⁰, OR¹¹, SH or S(O)_(n)R¹²; -   R² is selected from H, C₁–C₄ alkyl, C₂–C₄ alkenyl, C₂–C₄ alkynyl,     C₃–C₆ cycloalkyl, C₄–C₁₀ cycloalkylalkyl, C₁–C₄ hydroxyalkyl, halo,     CN, —NR⁶R⁷, NR⁹COR¹⁰, —NR⁶S(O)_(n)R⁷, S(O)_(n)NR⁶R⁷, C₁–C₄     haloalkyl, —OR⁷, SH or —S(O)_(n)R¹²; -   R³ is selected from:     -   —H, OR⁷, SH, S(O)_(n)R¹³, COR⁷, CO₂R⁷, OC(O)R¹³, NR⁸COR⁷,         N(COR⁷)₂, NR⁸CONR⁶R⁷, NR⁸CO₂R¹³, NR⁶R⁷, NR^(6a)R^(7a), N(OR⁷)R⁶,         CONR⁶R⁷, aryl, heteroaryl and heterocyclyl, or     -   —C₁–C₁₀ alkyl, C₂–C₁₀ alkenyl, C₂–C₁₀ alkynyl, C₃–C₈ cycloalkyl,         C₅–C₈ cycloalkenyl, C₄–C₁₂ cycloalkylalkyl or C₆–C₁₀         cycloalkenylalkyl, each optionally substituted with 1 to 3         substituents independently selected at each occurrence from         C₁–C₆ alkyl, C₃–C₆ cycloalkyl, halo, C₁–C₄ haloalkyl, cyano,         OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵,         N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl,         heteroaryl and heterocyclyl; -   R⁴ is independently selected at each occurrence from: C₁–C₁₀ alkyl,     C₂–C₁₀ alkenyl, C₂–C₁₀ alkynyl, C₃–C₆ cycloalkyl, C₄–C₁₂     cycloalkylalkyl, NO₂, halo, CN, C₁–C₄ haloalkyl, NR⁶R⁷, NR⁸COR⁷,     NR⁸CO₂R⁷, COR⁷, OR⁷, CONR⁶R⁷, C(NOR⁹)R⁷, CO₂R⁷, or S(O)_(n)R⁷, where     each such C₁–C₁₀ alkyl, C₂–C₁₀ alkenyl, C₂–C₁₀ alkynyl, C₃–C₆     cycloalkyl and C₄–C₁₂ cycloalkylalkyl are optionally substituted     with 1 to 3 substituents independently selected at each occurrence     from C₁–C₄ alkyl, NO₂, halo, CN, NR⁶R⁷, NR⁸COR⁷, NR⁸CO₂R⁷, COR⁷ OR⁷,     CONR⁶R⁷, CO₂R⁷, CO(NOR⁹)R⁷, or S(O)_(n)R⁷; -   R⁶, R⁷, R^(6a) and R^(7a) are independently selected at each     occurrence from:     -   —H,     -   —C₁–C₁₀ alkyl, C₃–C₁₀ alkenyl, C₃–C₁₀ alkynyl, C₁–C₁₀ haloalkyl         with 1–10 halogens, C₂–C₈ alkoxyalkyl, C₃–C₆ cycloalkyl, C₄–C₁₂         cycloalkylalkyl, C₅–C₁₀ cycloalkenyl, or C₆–C₁₄         cycloalkenylalkyl, each optionally substituted with 1 to 3         substituents independently selected at each occurrence from         C₁–C₆ alkyl, C₃–C₆ cycloalkyl, halo, C₁–C₄ haloalkyl, cyano,         OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵,         N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl,         heteroaryl or heterocyclyl,     -   -aryl, aryl(C₁–C₄ alkyl), heteroaryl, heteroaryl(C₁–C₄ alkyl),         heterocyclyl or heterocyclyl(C₁–C₄ alkyl); -   alternatively, NR⁶R⁷ and NR^(6a) R^(7a) are independently     piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine     or thiomorpholine, each optionally substituted with 1–3 C₁–C₄ alkyl     groups; -   R⁸ is independently selected at each occurrence from H or C₁–C₄     alkyl; -   R⁹ and R¹⁰ are independently selected at each occurrence from H,     C₁–C₄ alkyl, or C₃–C₆ cycloalkyl; -   R¹¹ is selected from H, C₁–C₄ alkyl, C₁–C₄ haloalkyl, or C₃–C₆     cycloalkyl; -   R¹² is C₁–C₄ alkyl or C₁–C₄ haloalkyl; -   R¹³ is selected from C₁–C₄ alkyl, C₁–C₄ haloalkyl, C₂–C₈     alkoxyalkyl, C₃–C₆ cycloalkyl, C₄–C₁₂ cycloalkylalkyl, aryl,     aryl(C₁–C₄ alkyl)-, heteroaryl or heteroaryl(C₁–C₄ alkyl)-; -   R¹⁴ is selected from C₁–C₁₀ alkyl, C₃–C₁₀ alkenyl, C₃–C₁₀ alkynyl,     C₃–C₈ cycloalkyl, or C₄–C₁₂ cycloalkylalkyl, each optionally     substituted with 1 to 3 substituents independently selected at each     occurrence from C₁–C₆ alkyl, C₃–C₆ cycloalkyl, halo, C₁–C₄     haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹⁵, COR¹⁵, CO₂R¹⁵, OC(O)R¹⁵,     NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹⁵, NR¹⁶R¹⁵, CONR¹⁶R¹⁵,     and C₁–C₆ alkylthio, C₁–C₆ alkylsulfinyl and C₁–C₆ alkylsulfonyl; -   R¹⁵ and R¹⁶ are independently selected at each occurrence from H,     C₁–C₆ alkyl, C₃–C₁₀ cycloalkyl, C₄–C₁₆ cycloalkylalkyl, except that     for S(O)_(n)R¹⁵, R¹⁵ cannot be H; -   aryl is phenyl or naphthyl, each optionally substituted with 1 to 5     substituents independently selected at each occurrence from C₁–C₆     alkyl, C₃–C₆ cycloalkyl, halo, C₁–C₄ haloalkyl, cyano, OR¹⁵, SH,     S(O)_(n)R¹⁵ COR¹⁵, CO₂R¹⁵, OC(O)R¹⁵, NR⁸COR¹⁵, N(COR¹⁵)₂,     NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹⁵ NR¹⁶R¹⁵, and CONR¹⁶R¹⁵; -   heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, pyranyl,     quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl,     pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl,     isoxazolyl, pyrazolyl, 2,3-dihydrobenzothienyl or     2,3-dihydrobenzofuranyl, each being optionally substituted with 1 to     5 substituents independently selected at each occurrence from C₁–C₆     alkyl, C₃–C₆ cycloalkyl, halo, C₁–C₄ haloalkyl, cyano, OR¹⁵, SH,     S(O)_(n)R¹⁵, —COR¹⁵, CO₂R¹⁵, OC(O)R¹⁵, NR⁸COR¹⁵, N(COR¹⁵)₂,     NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹⁵, NR¹⁶R¹⁵, and CONR¹⁶R¹⁵; -   heterocyclyl is saturated or partially saturated heteroaryl,     optionally substituted with 1 to 5 substituents independently     selected at each occurrence from C₁–C₆ alkyl, C₃–C₆ cycloalkyl,     halo, C₁–C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹⁵, COR¹⁵, CO₂R¹⁵,     OC(O)R¹⁵, NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹⁵, NR¹⁵R¹⁶, and     CONR¹⁶R¹⁵; -   n is independently at each occurrence 0, 1 or 2; -   with the proviso that when Z is CR², then R³ is not NR⁶R⁷,     NR^(6a)R^(7a) or OR⁷.

Further preferred methods of the present invention are methods wherein in the compound of Formulae (1) or (2), Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, each optionally substituted with 1 to 4 R⁴ substituents.

Further preferred methods of the present invention are methods wherein in the compound of Formulae (1) or (2), A is N, Z is CR², Ar is 2,4-dichlorophenyl, 2,4-dimethylphenyl or 2,4,6-trimethylphenyl, R¹ and R² are CH₃, and R³ is NR^(6a)R^(7a).

The present invention further comprises compounds of Formulae (1) or (2):

and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt forms thereof wherein:

-   Z is N or CR²; -   Ar is selected from phenyl, naphthyl, pyridyl, pyrimidinyl,     triazinyl, furanyl, thienyl, benzothienyl, benzofuranyl,     2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, indanyl,     1,2-benzopyranyl, 3,4-dihydro-1,2-benzopyranyl, tetralinyl, each Ar     optionally substituted with 1 to 5 R⁴ groups and each Ar is attached     to an unsaturated carbon atom; -   R¹ is independently selected at each occurrence from H, C₁–C₄ alkyl,     C₂–C₄ alkenyl, C₂–C₄ alkynyl, halo, CN, C₁–C₄ haloalkyl, C₁–C₁₂     hydroxyalkyl, C₂–C₁₂ alkoxyalkyl, C₂–C₁₀ cyanoalkyl, C₃–C₆     cycloalkyl, C₄–C₁₀ cycloalkylalkyl, NR⁹R¹⁰, C₁–C₄ alkyl-NR⁹R¹⁰,     NR⁹COR¹⁰, OR¹¹, SH or S(O)_(n)R¹²; -   R² is selected from H, C₁–C₄ alkyl, C₂–C₄ alkenyl, C₂–C₄ alkynyl,     C₃–C₆ cycloalkyl, C₄–C₁₀ cycloalkylalkyl, C₁–C₄ hydroxyalkyl, halo,     CN, —NR⁶R⁷, NR⁹COR¹⁰, —NR⁶S(O)_(n)R⁷, S(O)_(n)NR⁶R⁷, C₁–C₄     haloalkyl, —OR⁷, SH or —S(O)_(n)R¹²; -   R³ is selected from:     -   —H, OR⁷, SH, S(O)_(n)R¹³, COR⁷, CO₂R⁷, OC(O)R¹³, NR⁸COR⁷,         N(COR⁷)₂, NR⁸CONR⁶R⁷, NR⁸CO₂R¹³, NR⁶R⁷, NR^(6a)R^(7a), N(OR⁷)R⁶,         CONR⁶R⁷, aryl, heteroaryl and heterocyclyl, or     -   —C₁–C₁₀ alkyl, C₂–C₁₀ alkenyl, C₂–C₁₀ alkynyl, C₃–C₈ cycloalkyl,         C₅–C₈ cycloalkenyl, C₄–C₁₂ cycloalkylalkyl or C₆–C₁₀         cycloalkenylalkyl, each optionally substituted with 1 to 3         substituents independently selected at each occurrence from         C₁–C₆ alkyl, C₃–C₆ cycloalkyl, halo, C₁–C₄ haloalkyl, cyano,         OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵,         N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl,         heteroaryl and heterocyclyl; -   R⁴ is independently selected at each occurrence from: C₁–C₁₀ alkyl,     C₂–C₁₀ alkenyl, C₂–C₁₀ alkynyl, C₃–C₆ cycloalkyl, C₄–C₁₂     cycloalkylalkyl, NO₂, halo, CN, C₁–C₄ haloalkyl, NR⁶R⁷, NR⁸COR⁷,     NR⁸CO₂R⁷, COR⁷, OR⁷, CONR⁶R⁷, CO(NOR⁹)R⁷, CO₂R⁷, or S(O)_(n)R⁷,     where each such C₁–C₁₀ alkyl, C₂–C₁₀ alkenyl, C₂–C₁₀ alkynyl, C₃–C₆     cycloalkyl and C₄–C₁₂ cycloalkylalkyl are optionally substituted     with 1 to 3 substituents independently selected at each occurrence     from C₁–C₄ alkyl, NO₂, halo, CN, NR⁶R⁷, NR⁸COR⁷, NR⁸CO₂R⁷, COR⁷ OR⁷,     CONR⁶R⁷, CO₂R⁷, CO(NOR⁹)R⁷, or S(O)_(n)R⁷; -   R⁶, R⁷, R^(6a) and R^(7a) are independently selected at each     occurrence from:     -   —H,     -   —C₁–C₁₀ alkyl, C₃–C₁₀ alkenyl, C₃–C₁₀ alkynyl, C₁–C₁₀ haloalkyl         with 1–10 halogens, C₂–C₈ alkoxyalkyl, C₃–C₆ cycloalkyl, C₄–C₁₂         cycloalkylalkyl, C₅–C₁₀ cycloalkenyl, or C₆–C₁₄         cycloalkenylalkyl, each optionally substituted with 1 to 3         substituents independently selected at each occurrence from         C₁–C₆ alkyl, C₃–C₆ cycloalkyl, halo, C₁–C₄ haloalkyl, cyano,         OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵,         N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl,         heteroaryl or heterocyclyl,     -   -aryl, aryl(C₁–C₄ alkyl), heteroaryl, heteroaryl(C₁–C₄ alkyl),         heterocyclyl or heterocyclyl(C₁–C₄ alkyl); -   alternatively, NR⁶R⁷ and NR^(6a)R^(7a) are independently piperidine,     pyrrolidine, piperazine, N-methylpiperazine, morpholine or     thiomorpholine, each optionally substituted with 1–3 C₁–C₄ alkyl     groups; -   R⁸ is independently selected at each occurrence from H or C₁–C₄     alkyl; -   R⁹ and R¹⁰ are independently selected at each occurrence from H,     C₁–C₄ alkyl, or C₃–C₆ cycloalkyl; -   R¹¹ is selected from H, C₁–C₄ alkyl, C₁–C₄ haloalkyl, or C₃–C₆     cycloalkyl; -   R¹² is C₁–C₄ alkyl or C₁–C₄ haloalkyl; -   R¹³ is selected from C₁–C₄ alkyl, C₁–C₄ haloalkyl, C₂–C₈     alkoxyalkyl, C₃–C₆ cycloalkyl, C₄–C₁₂ cycloalkylalkyl, aryl,     aryl(C₁–C₄ alkyl)-, heteroaryl or heteroaryl(C₁–C₄ alkyl)-; -   R¹⁴ is selected from C₁–C₁₀ alkyl, C₃–C₁₀ alkenyl, C₃–C₁₀ alkynyl,     C₃–C₈ cycloalkyl, or C₄–C₁₂ cycloalkylalkyl, each optionally     substituted with 1 to 3 substituents independently selected at each     occurrence from C₁–C₆ alkyl, C₃–C₆ cycloalkyl, halo, C₁–C₄     haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹⁵, COR¹⁵, CO₂R¹⁵, OC(O)R¹⁵,     NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹⁵, NR¹⁶R¹⁵, CONR¹⁶R¹⁵,     and C₁–C₆ alkylthio, C₁–C₆ alkylsulfinyl and C₁–C₆ alkylsulfonyl; -   R¹⁵ and R¹⁶ are independently selected at each occurrence from H,     C₁–C₆ alkyl, C₃–C₁₀ cycloalkyl, C₄–C₁₆ cycloalkylalkyl, except that     for S(O)_(n)R¹⁵, R¹⁵ cannot be H; -   aryl is phenyl or naphthyl, each optionally substituted with 1 to 5     substituents independently selected at each occurrence from C₁–C₆     alkyl, C₃–C₆ cycloalkyl, halo, C₁–C₄ haloalkyl, cyano, OR¹⁵, SH,     S(O)_(n)R¹⁵, COR¹⁵, CO₂R¹⁵, OC(O)R¹⁵, NR⁸COR¹⁵, N(COR¹⁵)₂,     NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹⁵, NR¹⁶R¹⁵, and CONR¹⁶R¹⁵; -   heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, pyranyl,     quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl,     pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl,     isoxazolyl, pyrazolyl, 2,3-dihydrobenzothienyl or     2,3-dihydrobenzofuranyl, each being optionally substituted with 1 to     5 substituents independently selected at each occurrence from C₁–C₆     alkyl, C₃–C₆ cycloalkyl, halo, C₁–C₄ haloalkyl, cyano, OR¹⁵, SH,     S(O)_(n)R¹⁵, —COR¹⁵, CO₂R¹⁵, OC(O)R¹⁵, NR⁸COR¹⁵, N(COR¹⁵)₂,     NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹⁵, NR¹⁶R¹⁵, and CONR¹⁶R¹⁵; -   heterocyclyl is saturated or partially saturated heteroaryl,     optionally substituted with 1 to 5 substituents independently     selected at each occurrence from C₁–C₆ alkyl, C₃–C₆ cycloalkyl,     halo, C₁–C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹⁵, COR¹⁵, CO₂R¹⁵,     OC(O)R¹⁵, NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹⁵, NR¹⁵R¹⁶, and     CONR¹⁶R¹⁵; -   n is independently at each occurrence 0, 1 or 2; -   with the provisos that:     -   (1) when Z is CR² and R² is H and R³ is OCOR¹³ and R⁷ is H, then         R¹ is not H, OH or SH;     -   (2) when Z is CR² and R¹ is CH₃ or C₂H₅ and R² is H, and R³ is         H, CH₃, C₂H₅, C₆H₅, n-C₃H₇, i-C₃H₇, SH or SCH₃, then Ar is not         phenyl or m-CH₃-phenyl;     -   (3) when Z is CR² and R² is —NR⁶SO₂R⁷ or —SO₂NR⁶R⁷, then R³ is         not SH; and     -   (4) when Z is CR₂, then R³ is not NR⁶R⁷, NR^(6a)R^(7a) or OR⁷.

Further preferred compounds of the present invention include compounds of formula (1) or (2) and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt forms thereof wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, each optionally substituted with 1 to 4 R⁴ substituents.

The present invention further provides for a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (1) or 2.

Further preferred compounds of the present invention include compounds of Formula (2) and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt forms thereof.

Further preferred compounds of the present invention include compounds of formula (2) and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt forms thereof wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl and each Ar is optionally substituted with 1 to 4 R⁴ substituents.

Further preferred compounds of the present invention include compounds of formula (2) and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt forms thereof wherein R³ is NR^(6a)R^(7a) or OR⁷.

Further preferred compounds of the present invention include compounds of formula (2) and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt forms thereof wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to 4 R⁴ substituents, and R³ is NR^(6a)R^(7a) or OR⁷.

Further preferred compounds of the present invention include compounds of formula (1) or (2) and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt forms thereof wherein Z is CR².

Further preferred compounds of the present invention include compounds of formula (1) and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt forms thereof wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl and each Ar is optionally substituted with 1 to 4 R⁴ substituents.

Further preferred compounds of the present invention include compounds of formula (1) or (2) and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt forms thereof wherein:

-   R^(6a) is independently selected from:     -   —H,     -   —C₁–C₁₀ alkyl, C₃–C₁₀ alkenyl, C₃–C₁₀ alkynyl, C₁–C₁₀ haloalkyl         with 1–10 halogens, C₂–C₈ alkoxyalkyl, C₃–C₆ cycloalkyl, C₄–C₁₂         cycloalkylalkyl, C₁–C₁₀ cycloalkenyl, or C₆–C₁₄         cycloalkenylalkyl, each optionally substituted with 1 to 3         substituents independently selected at each occurrence from         C₁–C₆ alkyl, C₃–C₆ cycloalkyl, halo, C₁–C₄ haloalkyl, cyano,         OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵,         N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl,         heteroaryl or heterocyclyl,     -   -aryl, aryl(C₁–C₄ alkyl), heteroaryl, heteroaryl(C₁–C₄ alkyl),         heterocyclyl or heterocyclyl(C₁–C₄ alkyl); and -   R^(7a) is independently selected at each occurrence from:     -   —H,     -   —C₅–C₁₀ alkyl, C₃–C₁₀ alkenyl, C₃–C₁₀ alkynyl, C₁–C₁₀ haloalkyl         with 1–10 halogens, C₂–C₈ alkoxyalkyl, C₃–C₆ cycloalkyl, C₄–C₁₂         cycloalkylalkyl, C₅–C₁₀ cycloalkenyl, or C₆–C₁₄         cycloalkenylalkyl, each optionally substituted with 1 to 3         substituents independently selected at each occurrence from         C₁–C₆ alkyl, C₃–C₆ cycloalkyl, halo, C₁–C₄ haloalkyl, cyano,         OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵,         N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl,         heteroaryl or heterocyclyl,     -   -aryl, aryl(C₁–C₄ alkyl), heteroaryl, heteroaryl(C₁–C₄ alkyl),         heterocyclyl or heterocyclyl(C₁–C₄ alkyl); -   alternatively, NR⁶R⁷ and NR^(6a)R^(7a) are independently piperidine,     pyrrolidine, piperazine, N-methylpiperazine, morpholine or     thiomorpholine, each optionally substituted with 1–3 C₁–C₄ alkyl     groups.

Further preferred compounds of the present invention include compounds of formula (1) or (2) and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt forms thereof wherein:

-   R^(6a) and R^(7a) are identical and are selected from:     -   —C₁–C₄ alkyl or C₃–C₆ cycloalkyl, each optionally substituted         with 1 to 3 substituents independently selected at each         occurrence from C₁–C₆ alkyl, C₃–C₆ cycloalkyl, halo, C₁–C₄         haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹³, —COR¹⁵, CO₂R¹⁵,         OC(O)R¹³, NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵,         CONR¹⁶R¹⁵, aryl, heteroaryl or heterocyclyl, and -aryl or         heteroaryl.

Further preferred compounds of the present invention include compounds of formula (1) or (2) and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt forms thereof wherein:

-   R^(6a) is selected from:     -   —H,     -   —C₁–C₁₀ alkyl, C₃–C₁₀ alkenyl, C₃–C₁₀ alkynyl, C₁–C₁₀ haloalkyl         with 1–10 halogens, C₂–C₈ alkoxyalkyl, C₃–C₆ cycloalkyl, C₄–C₁₂         cycloalkylalkyl, C₁–C₁₀ cycloalkenyl, or C₆–C₁₄         cycloalkenylalkyl, each optionally substituted with 1 to 3         substituents independently selected at each occurrence from         C₁–C₆ alkyl, C₃–C₆ cycloalkyl, halo, C₁–C₄ haloalkyl, cyano,         OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵,         N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl,         heteroaryl or heterocyclyl,     -   -aryl, aryl(C₁–C₄ alkyl), heteroaryl, heteroaryl(C₁–C₄ alkyl),         heterocyclyl or heterocyclyl(C₁–C₄ alkyl); -   R^(7a) is selected from:     -   —C₁–C₄ alkyl and each such C₁–C₄ alkyl is substituted with 1–3         substituents independently selected at each occurrence from         C₁–C₆ alkyl, C₃–C₆ cycloalkyl, halo, C₁–C₄ haloalkyl, cyano,         OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵,         N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl,         heteroaryl or heterocyclyl.

Further preferred compounds of the present invention include compounds of formula (1) or (2) and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt forms thereof wherein:

-   one of R^(6a) and R^(7a) is selected from:     -   —C₃–C₆ cycloalkyl, each such C₃–C₆ cycloalkyl optionally         substituted with 1–3 substituents independently selected at each         occurrence from C₁–C₆ alkyl, C₃–C₆ cycloalkyl, halo, C₁–C₄         haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵,         OC(O)R¹³, NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵,         CONR¹⁶R¹⁵, aryl, heteroaryl or heterocyclyl,     -   -aryl,     -   -heteroaryl or     -   -heterocyclyl,         and the other of R^(6a) and R^(7a) is unsubstituted C₁–C₄ alkyl.

Further preferred compounds of the present invention include compounds of formula (1) of (2) and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt forms thereof wherein R^(6a) and R^(7a) are independently H or C₁–C₁₀ alkyl, each such C₁–C₁₀ alkyl optionally substituted with 1 to 3 substituents independently selected at each occurrence from C₁–C₆ alkyl, C₃–C₆ cycloalkyl, halo, C₁–C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵, N(COR¹⁵)₂, R⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl, heteroaryl or heterocyclyl.

Further preferred compounds of the present invention include compounds of formula (1) or (2) and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt forms thereof wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to 4 R⁴ substituents.

Further preferred compounds of the present invention include compounds of formula (1) or (2) and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt forms thereof wherein

-   -   —Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar         is optionally substituted with 1 to 4 R⁴ substituents,     -   —R¹ and R² are independently selected from H, C₁–C₄ alkyl, C₃–C₆         cycloalkyl, C₄–C₁₀ cycloalkylalkyl.

Further preferred compounds of the present invention include compounds of formula (1) or (2) and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt forms thereof wherein R^(6a) and R^(7a) are independently H or C₁–C₁₀ alkyl, each such C₁–C₁₀ alkyl optionally substituted with 1 to 3 substituents independently selected at each occurrence from C₁–C₆ alkyl, C₃–C₆ cycloalkyl, halo, C₁–C₄ haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵, OC(O)R¹³, NR⁸COR¹⁵, N(COR¹⁵)₂, R⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl, heteroaryl or heterocyclyl.

Further preferred compounds of the present invention include compounds of formula (1) or (2) and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt forms thereof wherein R¹ is independently selected at each occurrence from H, C₁–C₄ alkyl, C₂–C₄ alkenyl, C₂–C₄ alkynyl, halo, CN, C₁–C₄ haloalkyl, C₁–C₁₂ hydroxyalkyl, C₂–C₁₂ alkoxyalkyl, C₃–C₆ cycloalkyl, C₄–C₁₀ cycloalkylalkyl.

Further preferred compounds of the present invention include compounds formula (1) or (2) and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt forms thereof wherein R² is selected from H, C₁–C₄ alkyl, C₂–C₄ alkenyl, C₂–C₄ alkynyl, C₃–C₆ cycloalkyl, C₄–C₁₀ cycloalkylalkyl, C₁–C₄ hydroxyalkyl, halo, CN, —NR⁶R⁷, C₁–C₄ haloalkyl, —OR⁷.

Further preferred compounds of the present invention include compounds of formula (1) or (2) and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt forms thereof wherein R⁴ is independently selected at each occurrence from: C₁–C₁₀ alkyl, C₂–C₁₀ alkenyl, C₃–C₆ cycloalkyl, C₄–C₁₂ cycloalkylalkyl, halo, CN, C₁–C₄ haloalkyl, NR⁶R⁷, COR⁷, OR⁷, where each such C₁–C₁₀ alkyl, C₂–C₁₀ alkenyl, C₂–C₃–C₆ cycloalkyl and C₄–C₁₂ cycloalkylalkyl are optionally substituted with 1 to 3 substituents independently selected at each occurrence from C₁–C₄ alkyl, NR⁶R⁷, COR⁷ OR⁷, CO₂R⁷.

Further preferred compounds of the present invention include compounds of formula (1) or (2) and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt forms thereof wherein R⁴ is independently selected at each occurrence from: H, C₁–C₁₀ alkyl, C₁–C₄ alkoxy, halo, CN and —NR⁶R⁷.

The present invention further provides for a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (1) or (2).

The present invention further provides for a method of treating affective disorder, anxiety, depression, headache, irritable bowel syndrome, posttraumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other feeding disorder, drug addiction, drug or alcohol withdrawal symptoms, inflammatory diseases, cardiovascular or heart-related diseases, fertility problems, human immunodeficiency virus infections, hemorrhagic stress, obesity, infertility, head and spinal cord traumas, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis, hypoglycemia or a disorder the treatment of which can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, in mammals comprising administering to the mammal a therapeutically effective amount of a compound of formula (1) or (2).

Many compounds of this invention have one or more asymmetric centers or planes. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms are included in the present invention. Many geometric isomers of olefins, C═N double bonds, and the like can also be present in the compounds, and all such stable isomers are contemplated in the present invention. The compounds may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. All chiral, (enantiomeric and diastereomeric) and racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated.

The term “alkyl” includes both branched and straight-chain alkyl having the specified number of carbon atoms. Commonly used abbreviations have the following meanings: Me is methyl, Et is ethyl, Pr is propyl, Bu is butyl. As is conventional, in a chemical structure drawing, a straight single bond attached to an atom at one end but with no atom designation at the other end indicates the presence of a methyl group at the unattached end of the bond. The prefix “n” means a straight chain alkyl. The prefix “c” means a cycloalkyl. The prefix “(S)” means the S enantiomer and the prefix “(R)” means the R enantiomer. Alkenyl” includes hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon—carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl, and the like. “Alkynyl” includes hydrocarbon chains of either a straight or branched configuration and one or more triple carbon—carbon bonds which may occur in any stable point along the chain, such as ethynyl, propynyl and the like. “Haloalkyl” is intended to include both branched and straight-chain alkyl having the specified number of carbon atoms, substituted with 1 or more halogen; “alkoxy” represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge; “cycloalkyl” is intended to include saturated ring groups, including mono-,bi- or poly-cyclic ring systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and so forth. “Halo” or “halogen” includes fluoro, chloro, bromo, and iodo.

The term “substituted”, as used herein, means that one or more hydrogen on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substitent is keto (i.e., ═O), then 2 hydrogens on the atom are replaced.

Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By “stable compound” or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

The term “appropriate amino acid protecting group” means any group known in the art of organic synthesis for the protection of amine or carboxylic acid groups. Such amine protecting groups include those listed in Greene and Wuts, “Protective Groups in Organic Synthesis” John Wiley & Sons, New York (1991) and “The Peptides: Analysis, Synthesis, Biology, Vol. 3, Academic Press, New York (1981), the disclosure of which is hereby incorporated by reference. Any amine protecting group known in the art can be used. Examples of amine protecting groups include, but are not limited to, the following: 1) acyl types such as formyl, trifluoroacetyl, phthalyl, and p-toluenesulfonyl; 2) aromatic carbamate types such as benzyloxycarbonyl (Cbz) and substituted benzyloxycarbonyls, 1-(p-biphenyl)-1-methylethoxycarbonyl, and 9-fluorenylmethyloxycarbonyl (Fmoc); 3) aliphatic carbamate types such as tert-butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl, and allyloxycarbonyl; 4) cyclic alkyl carbamate types such as cyclopentyloxycarbonyl and adamantyloxycarbonyl; 5) alkyl types such as triphenylmethyl and benzyl; 6) trialkylsilane such as trimethylsilane; and 7) thiol containing types such as phenylthiocarbonyl and dithiasuccinoyl.

The term “pharmaceutically acceptable salts” includes acid or base salts of the compounds of Formulae (1) and (2). Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.

Pharmaceutically acceptable salts of the compounds of the invention can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.

“Prodrugs” are considered to be any covalently bonded carriers which release the active parent drug of formula (I) or (II) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the compounds of formula (I) and (II) are prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds. Prodrugs include compounds wherein hydroxy, amine, or sulfhydryl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of formulas (I) and (II); and the like.

The term “therapeutically effective amount” of a compound of this invention means an amount effective to antagonize abnormal level of CRF or treat the symptoms of affective disorder, anxiety or depression in a host.

Syntheses

Some compounds of Formula (1) may be prepared from intermediate compounds of Formula (7), using the procedures outlined in Scheme 1:

Compounds of Formula (7) (where Y is O) may be treated with a halogenating agent or sulfonylating agent in the presence or absence of a base in the presence or absence of an inert solvent at reaction temperatures ranging from −80° C. to 250° C. to give products of Formula (8) (where X is halogen, alkanesulfonyloxy, arylsulfonyloxy or haloalkane-sulfonyloxy). Halogenating agents include, but are not limited to, SOCl₂, POCl₃, PCl₃, PCl₅, POBr₃, PBr₃ or PBr₅. Sulfonylating agents include, but are not limited to, alkanesulfonyl halides or anhydrides (such as methanesulfonyl chloride or methanesulfonic acid anhydride), arylsulfonyl halides or anhydrides (such as p-toluenesulfonyl chloride or anhydride) or haloalkylsulfonyl halides or anhydrides (preferably trifluoromethanesulfonic anhydride). Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons)(preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane). Preferred reaction temperatures range from −20° C. to 100° C.

Compounds of Formula (8) may be reacted with compounds of Formula R³H (where R³ is defined as above except R³ is not SH, COR⁷, CO₂R⁷, aryl or heteroaryl) in the presence or absence of a base in the presence or absence of an inert solvent at reaction temperatures ranging from −80 to 250° C. to generate compounds of Formula (1). Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal carbonates, alkali metal bicarbonates, alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane). Preferred reaction temperatures range from 0° C. to 140° C.

Scheme 2 delineates the procedures for converting intermediate compounds of Formula (7) (where Y is S) to some compounds of Formula (1).

Compounds of Formula (7) (where Y is S) may be treated with an alkylating agent R¹³X (where R¹³ is defined as above, except R¹³ is not aryl or heteroaryl) in the presence or absence of a base in the presence or absence of an inert solvent at reaction temperatures ranging from −80° C. to 250° C. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons)(preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal carbonates, alkali metal hydroxides, alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (prefereably N,N-di-isopropyl-N-ethyl amine or triethyl amine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane). Preferred reaction temperatures range from −80° C. to 100° C.

Compounds of Formula (12) (Formula (1) where R³ is SR¹³) may then be reacted with compounds of Formula R³H to give compounds of Formula (1), using the same conditions and reagents as were used for the conversion of compounds of Formula (8) to compounds of Formula (1) as outlined for Scheme 1 above. Alternatively, compounds of Formula (12) (Formula (1) where R³ is SR¹³) may be oxidized to compounds of Formula (13) (Formula (1) where R³ is S(O)_(n)R¹³, n is 1,2) by treatment with an oxidizing agent in the presence of an inert solvent at temperatures ranging from −80° C. to 250° C. Oxidizing agents include, but are not limited to, hydrogen peroxide, alkane or aryl peracids (preferably peracetic acid or m-chloroperbenzoic acid), dioxirane, oxone, or sodium periodate. Inert solvents may include, but are not limited to, alkanones (3 to 10 carbons, preferably acetone), water, alkyl alcohols (1 to 6 carbons), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane) or combinations thereof. The choices of oxidant and solvent are known to those skilled in the art (cf. Uemura, S., Oxidation of Sulfur, Selenium and Tellurium, in Comprehensive Organic Synthesis, Trost, B. M. ed., (Elmsford, N.Y.: Pergamon Press, 1991), 7, 762–769). Preferred reaction temperatures range from −20° C. to 100° C. Compounds of Formula (13) (Formula (1) where R³ is S(O)_(n)R¹³ n is 1,2) may then be reacted with compounds of Formula R³H to give compounds of Formula (1), using the same conditions and reagents as were used for the conversion of compounds of Formula (8) to compounds of Formula (1) as outlined for Scheme (1) above.

Compounds of Formula (1), where R³ may be —NR⁸COR⁷, —N(COR⁷)₂, —NR⁸CONR⁶R⁷, —NR⁸CO₂R¹³, —NR⁶R⁷, NR⁸SO₂R⁷, may be prepared from compounds of Formula (7), where Y is NH, by the procedures depicted in Scheme 3.

Reaction of compounds of Formula (7), where Y is NH, with alkylating agents, sulfonylating agents or acylating agents or sequential reactions with combinations thereof, in the presence or absence of a base in an inert solvent at reaction temperatures ranging from −80° C. to 250° C. may afford compounds of Formula (1), where R³ may be —NR⁸COR⁷, —N(COR⁷)₂, —NR⁸CONR⁶R⁷, —NR⁸CO₂R¹³, —NR⁶R⁷, —NR⁸SO₂R⁷. Alkylating agents may include, but are not limited to, C₁–C₁₀ alkyl -halides, -tosylates, -mesylates or -triflates; C₁–C₁₀ haloalkyl(1–10 halogens)-halides, -tosylates, -mesylates or -triflates; C₂–C₈ alkoxyalkyl-halides, -tosylates, -mesylates or -triflates; C₃–C₆ cycloalkyl-halides, -tosylates, -mesylates or -triflates; C₄–C₁₂ cycloalkylalkyl-halides, -tosylates, -mesylates or -triflates; aryl(C₁–C₄ alkyl)-halides, -tosylates, -mesylates or -triflates; heteroaryl(C₁–C₄ alkyl)-halides, -tosylates, -mesylates or -triflates; or heterocyclyl(C₁–C₄ alkyl)-halides, -tosylates, -mesylates or -triflates. Acylating agents may include, but are not limited to, C₁–C₁₀ alkanoyl halides or anhydrides, C₁–C₁₀ haloalkanoyl halides or anhydrides with 1–10 halogens, C₂–C₈ alkoxyalkanoyl halides or anhydrides, C₃–C₆ cycloalkanoyl halides or anhydrides, C₄–C₁₂ cycloalkylalkanoyl halides or anhydrides, aroyl halides or anhydrides, aryl(C₁–C₄) alkanoyl halides or anhydrides, heteroaroyl halides or anhydrides, heteroaryl(C₁–C₄) alkanoyl halides or anhydrides, heterocyclylcarboxylic acid halides or anhydrides or heterocyclyl(C₁–C₄) alkanoyl halides or anhydrides. Sulfonylating agents include, but are not limited to, C₁–C₁₀ alkylsulfonyl halides or anhydrides, C₁–C₁₀ haloalkylsulfonyl halides or anhydrides with 1–10 halogens, C₂–C₈ alkoxyalkylsulfonyl halides or anhydrides, C₃–C₆ cycloalkylsulfonyl halides or anhydrides, C₄–C₁₂ cycloalkylalkylsulfonyl halides or anhydrides, arylsulfonyl halides or anhydrides, aryl(C₁–C₄ alkyl)-, heteroarylsulfonyl halides or anhydrides, heteroaryl(C₁–C₄ alkyl)sulfonyl halides or anhydrides, heterocyclylsulfonyl halides or anhydrides or heterocyclyl(C₁–C₄ alkyl)sulfonyl halides or anhydrides. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons)(preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal carbonates, alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (prefereably di-isopropylethyl amine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from 0° C. to 100° C.

Scheme 4 delineates procedures, which may be employed to prepare intermediate compounds of Formula (7), where Y is O, S and Z is CR².

Compounds of the formula ArCH₂CN are reacted with compounds of the formula R²COR^(b), where R² is defined above and R^(b) is halogen, cyano, lower alkoxy (1 to 6 carbons) or lower alkanoyloxy (1 to 6 carbons), in the presence of a base in an inert solvent at reaction temperatures ranging from −78° C. to 200° C. to afford compounds of Formula (3). Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons)(preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal carbonates, alkali metal hydroxides, alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), water, dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from 0° C. to 100° C.

Compounds of Formula (3) may be treated with hydrazine-hydrate in the presence of an inert solvent at temperatures ranging from 0° C. to 200° C., preferably 70° C. to 150° C., to produce compounds of Formula (4). Inert solvents may include, but are not limited to, water, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Compounds of Formula (4) may be reacted with compounds of Formula (5) (where R^(c) is alkyl (1–6 carbons)) in the presence or absence of an acid in the presence of an inert solvent at temperatures ranging from 0° C. to 200° C. to produce compounds of Formula (6). Acids may include, but are not limited to alkanoic acids of 2 to 10 carbons (preferably acetic acid), haloalkanoic acids (2–10 carbons, 1–10 halogens, such as trifluoroacetic acid), arylsulfonic acids (preferably p-toluenesulfonic acid or benzenesulfonic acid), alkanesulfonic acids of 1 to 10 carbons (preferably methanesulfonic acid), hydrochloric acid, sulfuric acid or phosphoric acid. Stoichiometric or catalytic amounts of such acids may be used. Inert solvents may include, but are not limited to, water, alkanenitriles (1 to 6 carbons, preferably acetonitrile), halocarbons of 1 to 6 carbons and 1 to 6 halogens (preferably dichloromethane or chloroform), alkyl alcohols of 1 to 10 carbons (preferably ethanol), dialkyl ethers (4 to 12 carbons, preferably diethyl ether or di-isopropylether) or cyclic ethers such as dioxan or tetrahydrofuran. Preferred temperatures range from ambient temperature to 100° C.

Compounds of Formula (6) may be converted to intermediate compounds of Formula (7) by treatment with compounds C═Y(R^(d))₂ (where Y is O or S and R^(d) is halogen (preferably chlorine), alkoxy (1 to 4 carbons) or alkylthio (1 to 4 carbons)) in the presence or absence of a base in an inert solvent at reaction temperatures from −50° C. to 200° C. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons)(preferably sodium methoxide or sodium ethoxide), alkali metal carbonates, alkali metal hydroxides, trialkyl amines (preferably N,N-diisopropyl-N-ethyl amine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Preferred temperatures are 0° C. to 150° C.

Intermediate compounds of Formula (7), where Z is N, may be synthesized according the methods

Compounds of ArCH₂CN are reacted with compounds of Formula R^(q)CH₂N₃ (where R^(q) is a phenyl group optionally substituted by H, alkyl (1 to 6 carbons) or alkoxy (1 to 6 carbons) in the presence or absence of a base in an inert solvent at temperatures ranging from 0° C. to 200° C. to generate compounds of Formula (9). Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons)(preferably sodium methoxide, sodium ethoxide or potassium t-butoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal carbonates, alkali metal hydroxides, alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from ambient temperature to 100° C. Compounds of Formula (9) may be treated with a reducing agent in an inert solvent at 100° C. to 100° C. to afford products of Formula (10). Reducing agents include, but are not limited to, (a) hydrogen gas in combination with noble metal catalysts such as Pd-on-carbon, PtO₂, Pt-on-carbon, Rh-on-alumina or Raney nickel, (b) alkali metals (preferably sodium) in combination with liquid ammonia or (c) ceric ammonium nitrate. Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), water, dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). The preferred reaction temperatures are −50° C. to 60° C. Compounds of Formula (9) are then converted to compounds of Formula (7) (where Z is N) via intermediates of Formula (11) using the reagents and reaction conditions outlined in Scheme 4 for the conversion of compounds of Formula (4) to compounds of Formula (7) (where Z is CR²).

Compounds of Formula (1) may also be prepared from compounds of Formula (7) (where Y is O, S and Z is defined above) as outlined in Scheme 6:

Compounds of Formula (7) may be reacted with compounds of Formula R³H in the presence of a dehydrating agent in an inert solvent at reaction temperatures ranging from 0° C. to 250° C. Dehydrating agents include, but are not limited to, P₂O₅, molecular sieves or inorganic or organic acids. Acids may include, but are not limited to alkanoic acids of 2 to 10 carbons (preferably acetic acid), arylsulfonic acids (preferably p-toluenesulfonic acid or benzenesulfonic acid), alkanesulfonic acids of 1 to 10 carbons (preferably methanesulfonic acid), hydrochloric acid, sulfuric acid or phosphoric acid. Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably glyme or diglyme), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or halocarbons of 1 to 10 carbons and 1 to 10 halogens (preferably chloroform). Preferred reaction temperatures range from ambient temperature to 150° C.

Some compounds of Formula (1) (where A is N) may also be prepared by the methods shown in Scheme 7:

Intermediate compounds of Formula (14), where Z is defined above, may be reacted with compounds of Formula R³C(OR^(e))₃, where R^(e) may be alkyl (1 to 6 carbons) in the presence or absence of an acid in an inert solvent at temperatures ranging from 0° C. to 250° C. Acids may include, but are not limited to alkanoic acids of 2 to 10 carbons (preferably acetic acid), arylsulfonic acids (preferably p-toluenesulfonic acid or benzenesulfonic acid), alkanesulfonic acids of 1 to 10 carbons (preferably methanesulfonic acid), hydrochloric acid, sulfuric acid or phosphoric acid. Stoichiometric or catalytic amounts of such acids may be used. Inert solvents may include, but are not limited to, lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane). Preferred reaction temperatures range from 50° C. to 150° C.

Intermediate compounds of Formula (7) may also be synthesized by the reactions displayed in Scheme 8.

Compounds of Formula (15), (where Y is OH, SH, NR⁶R⁷; Z is defined above, X is Br, Cl, I, O₃SCF₃ or B(OR″″)₂ and R″″ is H or alkyl (1 to 6 carbons)) may be reacted with a compound of Formula ArM (where M is halogen, alkali metal, ZnCl, ZnBr, ZnI, MgBr, MgCl, MgI, CeCl₂, CeBr₂ or copper halides) in the presence or absence of an organometallic catalyst in the presence or absence of a base in an inert solvents at temperatures ranging from −100° C. to 200° C. Those skilled in the art will recognize that the reagents ArM may be generated in situ. Organometallic catalysts include, but are not limited to, palladium phosphine complexes (such as Pd(PPh₃)₄), palladium halides or alkanoates (such as PdCl₂(PPh₃)₂ or Pd(OAc)₂) or nickel complexes (such as NiCl₂(PPh₃)₂). Bases may include, but are not limited to, alkali metal carbonates or trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine). Inert solvents may include, but are not limited to, dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or water. Preferred reaction temperatures range from 80° C. to 100° C.

The choices of M and X are known to those skilled in the art (of Imamoto, T., Organocerium Reagents in Comprehensive Organic Synthesis, Trost, B. M. ed., (Elmsford, N.Y.: Pergamon Press, 1991), 1, 231–250; Knochel, P., Organozinc, Organocadmium and Organomercury Reagents in Comprehensive Organic Synthesis, Trost, B. M. ed., (Elmsford, N.Y.: Pergamon Press, 1991), 1, 211–230; Knight, D. W., Coupling Reactions between sp² Carbon Centers, in Comprehensive Organic Synthesis, Trost, B. M. ed., (Elmsford, N.Y.: Pergamon Press, 1991), 3, 481–520).

Compounds of Formula (1) may also be prepared using the methods shown in Scheme 9.

Compounds of Formula (16), where A, Z, R¹ and R³ are defined above and X is Br, Cl, I, O₃SCF₃ or B(OR″″)₂ and R″″ is H or alkyl (1 to 6 carbons)) may be reacted with a compound of Formula ArM (where M is halogen, alkali metal, ZnCl, ZnBr, ZnI, MgBr, MgCl, MgI, CeCl₂, CeBr₂ or copper halides) in the presence or absence of an organometallic catalyst in the presence or absence of a base in an inert solvents at temperatures ranging from −100° C. to 200° C. Those skilled in the art will recognize that the reagents ArM may be generated in situ (see the above references in Comprehensive Organic Synthesis). Organometallic catalysts include, but are not limited to, palladium phosphine complexes (such as Pd(PPh₃)₄), palladium halides or alkanoates (such as PdCl₂(PPh₃)₂ or Pd(OAc)₂) or nickel complexes (such as NiCl₂(PPh₃)₂). Bases may include, but are not limited to, alkali metal carbonates or trialkyl amines (preferably N,N-diisopropyl-N-ethyl amine or triethylamine). Inert solvents may include, but are not limited to, dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or water. Preferred reaction temperatures range from 80° C. to 100° C.

Intermediate compounds of Formula (7)(where Y is O, S, NH, Z is CR² and R¹, R² and Ar are defined as above) may be prepared as illustrated in Scheme 10.

Compounds of Formula (3) may be reacted with compounds of Formula H₂NNH(C═Y)NH₂, where Y is O, S or NH, in the presence or absence of a base or acid in an inert solvent at temperatures from 0° C. to 250° C. to produce compounds of Formula (17). Acids may include, but are not limited to alkanoic acids of 2 to 10 carbons (preferably acetic acid), arylsulfonic acids (preferably p-toluenesulfonic acid or benzenesulfonic acid), alkanesulfonic acids of 1 to 10 carbons (preferably methanesulfonic acid), hydrochloric acid, sulfuric acid or phosphoric acid. Stoichiometric or catalytic amounts of such acids may be used. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons)(preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 6 carbons), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane).

Preferred reaction temperatures range from 0° C. to 150° C. Compounds of Formula (17) may then be reacted with compounds of Formula R³C(OR^(e))₃, where R^(e) may be alkyl (1 to 6 carbons) in the presence or absence of an acid in an inert solvent at temperatures ranging from 0° C. to 250° C. Acids may include, but are not limited to alkanoic acids of 2 to 10 carbons (preferably acetic acid), arylsulfonic acids (preferably p-toluenesulfonic acid or benzenesulfonic acid), alkanesulfonic acids of 1 to 10 carbons (preferably methanesulfonic acid), hydrochloric acid, sulfuric acid or phosphoric acid. Stoichiometric or catalytic amounts of such acids may be used. Inert solvents may include, but are not limited to, lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane). Preferred reaction temperatures range from 50° C. to 150° C.

In Scheme 11, the procedures which may be used to convert compounds of Formula (1), where R³ is COR⁷, CO₂R⁷, NR⁸COR⁷ and CONR⁶R⁷, to other compounds of Formula (1), where R³ is CH(OH)R⁷, CH₂OH, NR⁸CH₂R⁷ and CH₂NR⁶R⁷ by treatment with a reducing agent in an inert solvent at temperatures ranging from −80° C. to 250° C.

Reducing agents include, but are not limited to, alkali metal or alkaline earth metal borohydrides (preferably lithium or sodium borohydride), borane, dialkylboranes (such as di-isoamylborane), alkali metal aluminum hydrides (preferably lithium aluminum hydride), alkali metal (trialkoxy)aluminum hydrides, or dialkyl aluminum hydrides (such as di-isobutylaluminum hydride). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 6 carbons), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from −80° C. to 100° C.

In Scheme 12, the procedures are shown which may be used to convert compounds of Formula (1), where R³ is COR⁷ or CO₂R⁷, to other compounds of Formula (1), where R³ is C(OH)(R⁷)₂ by treatment with a reagent of Formula R⁷M in an inert solvent at temperatures ranging from −80° C. to 250° C.

M is halogen, alkali metal, ZnCl, ZnBr, ZnI, MgBr, MgCl, MgI, CeCl₂, CeBr₂ or copper halides. Inert solvents may include, but are not limited to, dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran) or aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from −80° C. to 100° C.

Compounds of Formula (1), where R³ may be —NR⁸COR⁷, —N(COR⁷)₂, —NR⁸CONR⁶R⁷, —NR⁸CO₂R¹³, —NR⁶R⁷, —NR⁸SO₂R⁷, may be synthesized as depicted in Scheme 13.

Reaction of compounds of Formula (18), where R and R¹ are defined above, with compounds of Formula (4) or (10) in the presence or absence of base in an inert solvent may produce compounds of Formula (19) at temperatures ranging from −50° C. to 250° C. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal carbonates, alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (prefereably di-isopropylethyl amine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from 0° C. to 100° C.

Compounds of Formula (19) may then be reacted with alkylating agents, sulfonylating agents or acylating agents or sequential reactions with combinations thereof, in the presence or absence of a base in an inert solvent at reaction temperatures ranging from −80° C. to 250° C. may afford compounds of Formula (1), where R³ may be —NR⁸COR⁷, —N(COR⁷)₂, —NR⁸CONR⁶R⁷, —NR⁸CO₂R¹³, —NR⁶R⁷, —NR⁸SO₂R⁷. Alkylating agents may include, but are not limited to, C₁–C₁₀ alkyl -halides, -tosylates, -mesylates or -triflates; C₁–C₁₀ haloalkyl(1–10 halogens)-halides, -tosylates, -mesylates or -triflates; C₂–C₈ alkoxyalkyl-halides, -tosylates, -mesylates or -triflates; C₃–C₆ cycloalkyl-halides, -tosylates, -mesylates or -triflates; C₄–C₁₂ cycloalkylalkyl-halides, -tosylates, -mesylates or -triflates; aryl(C₁–C₄ alkyl)-halides, -tosylates, -mesylates or -triflates; heteroaryl(C₁–C₄ alkyl)-halides, -tosylates, -mesylates or -triflates; or heterocyclyl(C₁–C₄ alkyl)-halides, -tosylates, mesylates or -triflates. Acylating agents may include, but are not limited to, C₁–C₁₀ alkanoyl halides or anhydrides, C₁–C₁₀ haloalkanoyl halides or anhydrides with 1–10 halogens, C₂–C₈ alkoxyalkanoyl halides or anhydrides, C₃–C₆ cycloalkanoyl halides or anhydrides, C₄–C₁₂ cycloalkylalkanoyl halides or anhydrides, aroyl halides or anhydrides, aryl(C₁–C₄) alkanoyl halides or anhydrides, heteroaroyl halides or anhydrides, heteroaryl(C₁–C₄) alkanoyl halides or anhydrides, heterocyclylcarboxylic acid halides or anhydrides or heterocyclyl(C₁–C₄) alkanoyl halides or anhydrides. Sulfonylating agents include, but are not limited to, C₁–C₁₀ alkylsulfonyl halides or anhydrides, C₁–C₁₀ haloalkylsulfonyl halides or anhydrides with 1–10 halogens, C₂–C₈ alkoxyalkylsulfonyl halides or anhydrides, C₃–C₆ cycloalkylsulfonyl halides or anhydrides, C₄–C₁₂ cycloalkylalkylsulfonyl halides or anhydrides, arylsulfonyl halides or anhydrides, aryl(C₁–C₄ alkyl)-, heteroarylsulfonyl halides or anhydrides, heteroaryl(C₁–C₄ alkyl)sulfonyl halides or anhydrides, heterocyclylsulfonyl halides or anhydrides or heterocyclyl(C₁–C₄ alkyl)sulfonyl halides or anhydrides. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons)(preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal carbonates, alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (prefereably di-isopropylethyl amine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic-ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from 0° C. to 100° C.

Compounds of Formula (1), where A is CR and R is defined above, may be synthesized by the methods depicted in Scheme 14.

Compounds of Formula (4) or (10) may be treated with compounds of Formula (20), where R¹ and R³ are defined above in the presence or absence of base in an inert solvent at temperatures ranging from 0° C. to 250° C. to give compounds of Formula (1), where A is CR and R is defined above. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons)(preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal carbonates, alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (preferably di-isopropylethyl amine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from 0° C. to 100° C. Alternatively, compounds of Formula (1) where A is CR and R is defined above, may be synthesized through intermediates (22) and (23).

Compounds of Formula (4) or (10) may be treated with compounds of Formula (21), where R¹ is defined above and Re is alkyl (1–6 carbons), in the presence or absence of base in an inert solvent at temperatures ranging from 0° C. to 250° C. to give compounds of Formula (1), where A is CR and R is defined above. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons)(preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal carbonates, alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (prefereably di-isopropylethyl amine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from 0° C. to 100° C. Compounds of Formula (22) may be treated with a halogenating agent or sulfonylating agent in the presence or absence of a base in the presence or absence of an inert solvent at reaction temperatures ranging from −80° C. to 250° C. to give products of Formula (23) (where X is halogen, alkanesulfonyloxy, arylsulfonyloxy or haloalkane-sulfonyloxy). Halogenating agents include, but are not limited to, SOCl₂, POCl₃, PCl₃, PCl₅, POBr₃, PBr₃ or PBr₅. Sulfonylating agents include, but are not limited to, alkanesulfonyl halides or anhydrides (such as methanesulfonyl chloride or methanesulfonic acid anhydride), arylsulfonyl halides or anhydrides (such as p-toluenesulfonyl chloride or anhydride) or haloalkylsulfonyl halides or anhydrides (preferably trifluoromethanesulfonic anhydride). Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons)(preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane). Preferred reaction temperatures range from −20° C. to 100° C.

Compounds of Formula (23) may be reacted with compounds of Formula R³H (where R³ is defined as above except R³ is not SH, COR⁷, CO₂R⁷, aryl or heteroaryl) in the presence or absence of a base in the presence or absence of an inert solvent at reaction temperatures ranging from −80° C. to 250° C. to generate compounds of Formula (1). Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons)(preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal carbonates, alkali metal bicarbonates, alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane). Preferred reaction temperatures range from 0° C. to 140° C.

Some compounds of Formula (1) may also be prepared using the methods shown in Scheme 15.

A compound of Formula (24) (R_(c) is a lower alkyl group and Ar is defined as above) may be reacted with hydrazine in the presence or absence of an inert solvent to afford an intermediate of Formula (25), where Ar is defined as above. The conditions employed are similar to those used for the preparation of intermediate of Formula (4) from compound of Formula (3) in Scheme 4. Compounds of Formula (25), where A is N, may be reacted with reagents of the formula R¹C(═NH)OR_(e), where R¹ is defined above and R_(e) is a lower alkyl group) in the presence or absence of an acid in an inert solvent, followed by reaction with a compound of formula YisC(R_(d))2 (where Y is O or S and R^(d) is halogen (preferably chlorine), alkoxy (1 to 4 carbons) or alkylthio (1 to 4 carbons)) in the presence or absence of a base in an inert solvent to give compounds of Formula (27) (where A is N and Y is O, S). The conditions for these transformations are the same as those employed for the conversions of compound of Formula (4) to compound of Formula (7) in Scheme 4.

Alternatively, compounds of Formula (25), where A is CR, may be reacted with compounds of the formula R¹(C═O)CHR(C═Y)OR_(c) (where R¹ and R are defined as above and R_(c) is a lower alkyl group) to give a compound of Formula (27) (where A is CR) using conditions similar to those employed for the conversion of compounds of Formula (21) to compounds of Formula (22) in Scheme 14. Intermediates of Formula (27) (where Y is O) may be treated with halogenating agents or sulfonylating agents in the presence or absence of a base in an inert solvent, followed by reaction with R³H or R²H in the presence or absence of a base in an inert solvent to give compounds of Formula (1) (where Z is CR²).

It will be recognized by those skilled in the art that various combinations of halogenating agents, sulfonylating agents, R³H or R²H may be used in different orders of reaction sequences in Scheme 15 to afford compounds of Formula (1). For example, in some cases, it may be desirable to react compounds with stoichiometric amounts of halogenating agents or sulfonylating agents, react with R²H (or R³H), then repeat the reaction with halogenating agents or sulfonylating agents and react with R³H (or R²H) to give compounds of Formula (1). The reaction conditions and reagents used for these conversions are similar to the ones employed for the conversion of intermediate compounds of Formulae (22) to (23) to (1) in Scheme 14 (for A is CR) or the conversion of intermediate compounds of Formulae (7) to (8) to (1) in Scheme 1 (where A is N).

Alternatively, compounds of Formula (27) (where Y is S) may be converted to compounds of Formula (1) in Scheme 15. Intermediate compounds of Formula (27) may be alkylated with a compound R^(f)X (where R^(f) is lower alkyl and X is halogen, alkanesulfonyloxy or haloalkanesulfonyloxy) in an inert solvent, (then optionally oxidized with an oxidizing agent in an inert solvent) and then reacted with R³H in the presence or absence of a base in an inert solvent to give a compound of Formula (1). The conditions and reagents employed are similar to those used in the conversion of intermediate compounds of Formulae (7) to (12) (or to (13)) to compounds of Formula (1) in Scheme 2.

Compounds of Formula (1) may be prepared from compounds of Formula (24), using an alternate route as depicted in Scheme 15. Compounds of Formula (24) may be converted to compounds of Formula (27) via reaction with compounds of formula NH₂NH(C═NH)NH₂ in the presence or absence of an acid in an inert solvent, followed by reaction with compounds R¹C(OR_(c))₃ (where R_(c) is lower alkyl and R¹ is defined as above), using the conditions employed for the conversion of compounds of Formulae (3) to (17) to (7) in Scheme 10.

Some compounds of Formula (2) may be prepared by the methods illustrated in Scheme 16.

Compounds of Formula (27b) may be treated with various alkylating agents R¹⁴X (where R¹⁴ is defined above and X is halogen, alkanesulfonyloxy or haloalkanesulfonyloxy) in the presence or absence of a base in an inert solvent to afford structures of Formula (28). Compounds of Formula (28) (Y is O) may then be converted to compounds of Formula (2) by treatment with halogenating agents or sulfonylating agents in the presence or absence of a base in an inert solvent, followed by reaction with R³H in the presence or absence of a base in an inert solvent to give compounds of Formula (2). The reaction conditions used for these conversions are similar to the ones employed for the conversion of intermediate compounds (22) to (23) to (1) in Scheme 14 (for A is CR) or the conversion of intermediate compounds of Formulae (7) to (8) to (1) in Scheme 1 (where A is N). Alternatively, compounds of Formula (28) (Y is S) may be alkylated with a compound R^(f)X (where R^(f) is lower alkyl and X is halogen, alkanesulfonyloxy or haloalkanesulfonyloxy) in an inert solvent, (then optionally oxidized with an oxidizing agent in an inert solvent) and then reacted with R³H in the presence or absence of a base in an inert solvent to give a compound of Formula (1). The conditions and reagents employed are similar to those used in the conversion of intermediate compounds of Formulae (7) to (12) (or to (13)) to compounds of Formula (1) in Scheme 2.

Compounds of Formula (1), where Z is COH, may be converted to compounds of Formula (2) as illustrated in Scheme 16. Treatment with various alkylating agents R¹⁴X (where R¹⁴ is defined above and X is halogen, alkanesulfonyloxy or haloalkanesulfonyloxy) in the presence or absence of a base in an inert solvent to afford structures (2). It will be recognized by one skilled in the art that the methods used in Scheme 16 may also be used to prepare compounds of Formula (1) where Z is COR⁷.

For Scheme 16, the terms “base” and “inert solvent” may have the meanings given below. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons)(preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane). Preferred reaction temperatures range from −20° C. to 100° C.

EXAMPLES

Analytical data were recorded for the compounds described below using the following general procedures. Proton NMR spectra were recorded on an IBM-Bruker FT-NMR (300 MHz); chemical shifts were recorded in ppm (δ) from an internal tetramethysilane standard in deuterochloroform or deuterodimethylsulfoxide as specified below. Mass spectra (MS) or high resolution mass spectra (HRMS) were recorded on a Finnegan MAT 8230 spectrometer (using chemi-ionization (CI) with NH₃ as the carrier gas or gas chromatography (GC) as specified below) or a Hewlett Packard 5988A model spectrometer. Melting points were recorded on a Buchi Model 510 melting point apparatus and are uncorrected. Boiling points are uncorrected. All pH determinations during workup were made with indicator paper.

Reagents were purchased from commercial sources and, where necessary, purified prior to use according to the general procedures outlined by D. Perrin and W. L. F. Armarego, Purification of Laboratory Chemicals, 3rd ed., (New York: Pergamon Press, 1988). Chromatography was performed on silica gel using the solvent systems indicated below. For mixed solvent systems, the volume ratios are given. Otherwise, parts and percentages are by weight.

The following examples are provided to describe the invention in further detail. These examples, which set forth the best mode presently contemplated for carrying out the invention, are intended to illustrate and not to limit the invention.

Example 1 Preparation of 2,7-dimethyl-8-(2,4-dimethylphenyl)[1,5-a]-pyrazolo-[1,3,5]-triazin-4(3H)-one (Formula 7, where Y is O, R₁ is CH₃, Z is C—CH₃, Ar is 2,4-dimethylphenyl) A.1-Cyano-1-(2,4-dimethylphenyl)propan-2-one

Sodium pellets (9.8 g, 0.43 mol) were added portionwise to a solution of 2,4-dimethylphenylacetonitrile (48 g, 0.33 mol) in ethyl acetate (150 mL) at ambient temperature. The reaction mixture was heated to reflux temperature and stirred for 16 hours. The resulting suspension was cooled to room temperature and filtered. The collected precipitate was washed with copious amounts of ether and then air-dried. The solid was dissolved in water and a 1N HCl solution was added until the pH=5−6. The mixture was extracted with ethyl acetate (3×200 mL); the combined organic layers were dried over MgSO₄ and filtered. Solvent was removed in vacuo to afford a white solid (45.7 g, 74% yield): NMR (CDCl₃,300 MHz):; CI-MS: 188 (M+H).

B.5-Amino-4-(2,4-dimethylphenyl)-3-methylpyrazole

A mixture of 1-cyano-1-(2,4-dimethylphenyl)propan-2-one (43.8 g, 0.23 mol), hydrazine-hydrate (22 mL, 0.46 mol), glacial acetic acid (45 mL, 0.78 mol) and toluene (500 mL) were stirred at reflux temperature for 18 hours in an apparatus fitted with a Dean-Stark trap. The reaction mixture was cooled to ambient temperature and solvent was removed in vacuo. The residue was dissolved in 6N HCl and the resulting solution was extracted with ether three times. A concentrated ammonium hydroxide solution was added to the aqueous layer until pH=11. The resulting semi-solution was extracted three times with ethyl acetate. The combined organic layers were dried over MgSO₄ and filtered. Solvent was removed in vacuo to give a pale brown viscous oil (34.6 g, 75% yield): NMR (CDCl₃,300 MHz): 7.10 (s, 1H), 7.05 (d, 2H, J=1), 2.37 (s, 3H), 2.10 (s, 3H); CI-MS: 202 (M+H).

C.5-Acetamidino-4-(2,4-dimethylphenyl)-3-methylpyrazole, Acetic Acid Salt

Ethyl acetamidate hydrochloride (60 g, 0.48 mol) was added quickly to a rapidly stirred mixture of potassium carbonate (69.5 g, 0.50 mol), dichloromethane (120 mL) and water (350 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (2×120 mL). The combined organic layers were dried over MgSO₄ and filtered. Solvent was removed by simple distillation and the pot residue, a clear pale yellow liquid, (35.0 g) was used without further purification.

Glacial acetic acid (9.7 mL, 0.17 mol) was added to a stirred mixture of 5-amino-4-(2,4-dimethylphenyl)-3-methylpyrazole (34 g, 0.17 mol), ethyl acetamidate (22 g, 0.25 mol) and acetonitrile (500 mL). The resulting reaction mixture was stirred at room temperature for 3 days; at the end of which time, it was concentrated in vacuo to about one-third of its original volume. The resulting suspension was filtered and the collected solid was washed with copious amounts of ether. The white solid was dried in vacuo (31.4 g, 61% yield): NMR (DMSO-d₆, 300 MHz): 7.00 (s, 1H), 6.90 (dd, 2H, J=7, 1), 2.28 (s, 3H), 2.08 (s, 3H), 2.00 (s, 3H), 1.90 (s, 3H), 1.81 (s, 3H); CI-MS: 243 (M+H).

D.2,7-dimethyl-8-(2,4-dimethylphenyl)[1,5-a]pyrazolo-[1,3,5]-triazin-4(3H)-one

Sodium pellets (23 g, 1 mol) were added portionwise to ethanol (500 mL) with vigorous stirring. After all the sodium reacted, 5-acetamidino-4-(2,4-dimethylphenyl)-3-methylpyrazole, acetic acid salt (31.2 g, 0.1 mol) and diethyl carbonate (97 mL, 0.8 mol) were added. The resulting reaction mixture was heated to reflux temperature and stirred for 18 hours. The mix was cooled to room temperature and solvent was removed in vacuo. The residue was dissolved in water and a 1N HCl solution was added slowly until pH=5–6. The aqueous layer was extracted with ethyl acetate three times; the combined organic layers were dried over MgSO₄ and filtered. Solvent was removed in vacuo to give a pale tan solid (26 g, 98% yield): NMR (CDCl₃,300 MHz): 7.15(s, 1H), 7.09 (s, 2H), 2.45 (s, 3H), 2.39 (s, 3H), 2.30 (s, 3H); CI-MS: 269 (M+H).

Example 2 Preparation of 5-methyl-3-(2,4,6-trimethylphenyl)[1,5-a]-[1,2,3]-triazolo-[1,3,5]-triazin-7(6H)-one (Formula 7, where Y is 0, R₁ is CH₃, Z is N, Ar is 2,4,6-trimethylphenyl) A.1-Phenylmethyl-4-(2,4,6-trimethylphenyl)-5-aminotriazole

A mixture of 2,4,6-trimethylbenzyl cyanide (1.0 g, 6.3 mmol), benzyl azide (0.92 g, 6.9 mmol) and potassium t-butoxide (0.78 g, 6.9 mmol) in tetrahydrofuran (10 mL) was stirred at ambient temperature for 2.5 days. The resulting suspension was diluted with water and extracted three times with ethyl acetate. The combined organic layers were dried over MgSO₄ and filtered. Solvent was removed in vacuo to give a brown oil. Trituration with ether and filtration afforded a yellow solid (1.12 g, 61% yield): NMR (CDCl₃,300 MHz):7.60–7.30 (m, 5H), 7.30–7.20 (m, 2H), 5.50 (s, 2H), 3.18 (br s, 2H), 2.30 (s, 3H), 2.10 (s, 6H); CI-MS: 293 (M+H).

B.4-(2,4,6-Trimethylphenyl)-5-aminotriazole

Sodium (500 mg, 22 mmol) was added with stirring to a mixture of liquid ammonia (30 mL) and 1-phenylmethyl-4-(2,4,6-trimethylphenyl)-5-aminotriazole (1.1 g, 3.8 mmol). The reaction mixture was stirred until a dark green color persisted. An ammonium chloride solution (mL) was added and the mixture was stirred while warming to ambient temperature over 16 hours. The residue was treated with a 1M HCl solution and filtered. The aqueous layer was basified with a concentrated ammonium hydroxide solution (pH=9) and then extracted with ethyl acetate three times. The combined organic layers were dried over MgSO₄ and filtered. Solvent was removed in vacuo to give a yellow solid (520 mg), which was homogeneous by thin layer chromatography (ethyl acetate):

NMR (CDCl₃,300 MHz): 6.97 (s, 2H), 3.68–3.50 (br.s, 2H), 2.32 (s, 3H), 2.10 (s, 6H); CI-MS: 203 (M+H).

C.4-(2,4,6-Trimethylphenyl)-5-acetamidinotriazole, Acetic Acid Salt

A mixture of 4-(2,4,6-trimethylphenyl)-5-aminotriazole (400 mg, 1.98 mmol), ethyl acetamidate 261 mg, 3 mmol) and glacial acetic acid (0.1 mL, 1.98 mmol) in acetonitrile (6 mL) was stirred at ambient temperature for 4 hours. The resulting suspension was filtered and the collected solid was washed with copious amounts of ether. Drying in vacuo afforded a white solid (490 mg, 82% yield): NMR (DMSO-d₆,300 MHz):7.90–7.70 (br s, 0.5H), 7.50–7.20 (br. s, 0.5H), 6.90 (s, 2H), 6.90 (s, 2H), 3.50–3.10 (br s, 3H), 2.30–2.20 (br s, 3H), 2.05 (d, 1H, J=7), 1.96 (s, 6H), 1.87 (s, 6H); CI-MS: 244 (M+H).

D.5-methyl-3-(2,4,6-trimethylphenyl)[1,5-a][1,2,3]-triazolo-[1,3,5]-triazin-7(4H)-one

Sodium (368 mg, 16.2 mmol) was added with stirring to ethanol (10 mL) at room temperature. After the sodium had reacted, 4-(2,4,6-trimethylphenyl)-5-acetamidino-triazole, acetic acid salt (490 mg, 1.6 mmol) and diethyl carbonate (1.6 mL, 13 mmol) were added. The reaction mixture was stirred at reflux temperature for 5 hours, then cooled to room temperature. The reaction mixture was diluted with water; a 1N HCl solution was added until pH=5−6 and three extractions with ethyl acetate were performed. The combined organic layers were dried over MgSO₄ and filtered. Solvent was removed in vacuo to give a yellow residue. Trituration with ether and filtration afforded a yellow solid (300 mg, 69% yield): NMR (CDCl₃,300 MHz): 6.98 (s, 2H), 2.55 (s, 3H), 2.35 (s, 3H), 2.10 (s, 6H); CI-MS: 270 (M+H).

Example 3 Preparation of 4-(di(carbomethoxy)methyl)-2,7-dimethyl-8-(2,4-dimethylphenyl)[1,5-a]-pyrazolo 1,3,5-triazine (Formula 1, where R³ is CH(CHCO₂CH₃)₂, R₁ is CH₃, Z is C—CH₃, Ar is 2,4-dimethylphenyl) A. 4-chloro-2,7-dimethyl-8-(2,4-dichlorophenyl)[1,5-a]-pyrazolo-triazine

A mixture of 2,7-dimethyl-8-(2,4-dimethylphenyl)[1,5-a]-pyrazolo-1,3,5-triazin-4-one (Example 1, 1.38 g, 4.5 mmol), N,N-dimethylaniline (1 mL, 8 mmol) and phosphorus oxychloride (10 mL) was stirred at reflux temperature for 48 hours. The excess phosphorus oxychloride was removed in vacuo. The residue was poured onto ice-water, stirred briefly and extracted quickly with ethyl acetate three times. The combined organic layers were washed with ice water, then dried over MgSO₄ and filtered. Solvent was removed in vacuo to give a brown oil. Flash column chromatography (ethyl acetate:hexanes::1:4) gave one fraction (R_(f)=0.5) Solvent was removed in vacuo to afford a yellow oil (1.0 g, 68% yield): NMR (CDCl₃,300 MHz): 7.55 (d, 1H, J=1), 7.38 (dd, 1H, J=7,1), 7.30 (d, 1H, J=7), 2.68 (s, 3H), 2.45 (s, 3H); CI-MS: 327 (M+H).

B. 4-(di(carbomethoxy)methyl)-2,7-dimethyl-8-(2,4-dimethylphenyl)[1,5-a]-pyrazolo-1,3,5-triazine

Sodium hydride (60% in oil, 80 mg, 2 mmol) was washed with hexanes twice, decanted after each washing and taken up in anhydrous tetrahydrofuran (THF, 1 mL). A solution of diethyl malonate (0.32 g, 2 mmol) in THF (2 mL) was added dropwise over 5 min, during which time vigorous gas evolution ensued. A solution of 4-chloro-2,7-dimethyl-8-(2,4-dichlorophenyl)[1,5-a]pyrazolotriazine (0.5 g, 1.75 mmol) in THF (2 mL) was added and the reaction mixture was then stirred under a nitrogen atmosphere for 48 hours. The resulting suspension was poured onto water and extracted three times with ethyl acetate. The combined organic layers were washed once with brine, dried over MgSO₄ and filtered. Solvent was removed in vacuo to give a brown oil. Column chromatography (ethyl acetate:hexanes::1:9) afforded, after removal of solvent in vacuo, a pale yellow solid (Rf=0.2, 250 mg, 35% yield): mp 50–52° C.; NMR (CDCl₃, 300 MHz): 12.35 (br.s, 1H, 7.15–7.00 (m, 3H), 4.40 (q, 2H, J=7), 4.30 (q, 2H, J=7), 2.4, 2.35, 2.3, 2.2, 2.1 (5 s, 12H), 1.4 (t, 3H, J=7), 1.35–1.25 (m, 3H); CI-HRMS: Calcd: 411.2032, Found: 411.2023.

Example 6 Preparation of 4-(1,3-dimethoxy-2-propylamino)-2,7-dimethyl-8-(2,4-dichlorophenyl)[1,5-a]-pyrazolo 1,3,5-triazine (Formula 1, where R³ is NHCH(CH₂OCH₃)₂, R₁ is CH₃, Z is C—CH₃, Ar is 2,4-dichlorophenyl) A. 4-chloro-2,7-dimethyl-8-(2,4-dichlorophenyl)[1,5-a]-pyrazolotriazine

A mixture of 2,7-dimethyl-8-(2,4 dimethylphenyl)[1,5-a]-pyrazolo-1,3,5-triazin-4-one (Example 1, 1.38 g, 4.5 mmol), N,N-dimethylaniline (1 mL, 8 mmol) and phosphorus oxychloride (10 mL) was stirred at reflux temperature for 48 hours. The excess phosphorus oxychloride was removed in vacuo. The residue was poured onto ice-water, stirred briefly and extracted quickly with ethyl acetate three times. The combined organic layers were washed with ice water, then dried over MgSO₄ and filtered. Solvent was removed in vacuo to give a brown oil. Flash column chromatography (ethyl acetate:hexanes::1:4) gave one fraction (Rf=0.5) Solvent was removed in vacuo to afford a yellow oil (1.0 g, 68% yield): NMR (CDCl₃,300 MHz): 7.55 (d, 1H, J=1), 7.38 (dd, 1H, J=7,1), 7.30 (d, 1H, J=7), 2.68 (s, 3H), 2.45 (s, 3H); CI-MS: 327 (M+H).

B. 4-(1,3-dimethoxy-2-propylamino)-2,7-dimethyl-8-(2,4-dichlorophenyl)[1,5-a]-pyrazolo-1,3,5-triazine

A mixture of 4-chloro-2,7-dimethyl-8-(2,4-dichlorophenyl)[1,5-a]-pyrazolo-1,3,5-triazine (Part A, 570 mg, 1.74 mmol), 1,3-dimethoxypropyl-2-aminopropane (25 mg, 2.08 mmol) and ethanol (10 mL) was stirred at ambient temperature for 18 hours. The reaction mixture was poured onto water (25 mL) and extracted three times with ethyl acetate. The combined organic layers were dried over MgSO₄ and filtered. Solvent was removed in vacuo. Column chromatography (CH₂Cl₂:CH₃OH::50:1) afforded one fraction. Removal of solvent in vacuo gave a solid (250 mg, 35% yield): mp 118–120° C.; NMR (CDCl₃,300 MHz): 7.50 (s, 1H), 7.28 (dd, 2H, J=8,1), 6.75 (d, 1H, J=8), 4.70–4.58 (m, 1H), 3.70–3.55 (m, 4H), 3.43 (s, 6H), 2.50 (s, 3H), 2.35 (s, 3H); CI-HRMS: Calcd: 409.1072, Found: 409.1085; Analysis Calcd. for C₁₈H₂₁Cl₂N₅O₂: C, 52.69, H, 5.17, N, 17.07, Cl, 17.28; Found: C, 52.82, H, 5.06, N, 16.77, Cl, 17.50.

Using the above procedures and modifications known to one skilled in the art of organic synthesis, the following additional examples of Tables 1–4 may be prepared.

The examples delineated in TABLE 1 may be prepared by the methods outlined in Examples 1, 2, 3 or 6. Commonly used abbreviations are: Ph is phenyl, Pr is propyl, Me is methyl, Et is ethyl, Bu is butyl, Ex is Example.

TABLE 1

Ex. Z R₃ Ar mp(° C.)  6^(a) C—Me NHCH(CH₂OMe)₂ 2,4-Cl₂—Ph 118–120  7^(b) C—Me NHCHPr₂ 2,4-Cl₂—Ph 114–116  8^(c) C—Me NEtBu 2,4-Cl₂—Ph oil  9^(d) C—Me NPr(CH₂-c-C₃H₅) 2,4-Cl₂—Ph oil  10^(e) C—Me N(CH₂CH₂OMe)₂ 2,4-Cl₂—Ph oil  11^(f) C—Me NH-3-heptyl 2,4-Cl₂—Ph 90–92  12^(g) C—Me NHCH(Et)CH₂OMe 2,4-Cl₂—Ph 179–181  13^(h) C—Me NEt₂ 2,4-Cl₂—Ph 133–134  14^(i) C—Me NHCH(CH₂OEt)₂ 2,4-Cl₂—Ph oil  15^(j) C—Me NH-3-pentyl 2,4-Cl₂—Ph 139–140  16^(k) C—Me NMePh 2,4-Cl₂—Ph 60–62  17^(l) C—Me NPr₂ 2,4-Cl₂—Ph oil  18^(m) C—Me NH-3-hexyl 2,4-Cl₂—Ph 130–132  19 C—Me morpholino 2,4-Cl₂—Ph  20 C—Me N(CH₂Ph)CH₂CH₂OMe 2,4-Cl₂—Ph  21 C—Me NHCH(CH₂Ph)CH₂OMe 2,4-Cl₂—Ph  22 C—Me NH-4-tetrahydropyranyl 2,4-Cl₂—Ph  23 C—Me NH-cyclopentyl 2,4-Cl₂—Ph  24 C—Me 1,2,3,4-tetrahydro- 2,4-Cl₂—Ph isoquinolinyl  25 C—Me CH₂-(1,2,3,4-tetrahydro- 2,4-Cl₂—Ph isoquinolinyl)  26^(n) C—Me OEt 2,4-Cl₂—Ph 141–143  27 C—Me OCH(Et)CH₂OMe 2,4-Cl₂—Ph  28 C—Me OCH₂Ph 2,4-Cl₂—Ph  29 C—Me O-3-pentyl 2,4-Cl₂—Ph  30 C—Me SEt 2,4-Cl₂—Ph  31 C—Me S(O)Et 2,4-Cl₂—Ph  32 C—Me SO₂Et 2,4-Cl₂—Ph  33 C—Me CH(CO₂Et)₂ 2,4-Cl₂—Ph  34 C—Me C(Et)(CO₂Et)₂ 2,4-Cl₂—Ph  35 C—Me CH(Et)CH₂OH 2,4-Cl₂—Ph  36 C—Me CH(Et)CH₂OMe 2,4-Cl₂—Ph  37 C—Me CONMe₂ 2,4-Cl₂—Ph  38 C—Me COCH₃ 2,4-Cl₂—Ph  39 C—Me CH(OH)CH₃ 2,4-Cl₂—Ph  40 C—Me C(OH)Ph-3-pyridyl 2,4-Cl₂—Ph  41 C—Me Ph 2,4-Cl₂—Ph  42 C—Me 2-CF₃—Ph 2,4-Cl₂—Ph  43 C—Me 2-Ph—Ph 2,4-Cl₂—Ph  44 C—Me 3-pentyl 2,4-Cl₂—Ph  45 C—Me cyclobutyl 2,4-Cl₂—Ph  46 C—Me 3-pyridyl 2,4-Cl₂—Ph  47 C—Me CH(Et)CH₂CONMe₂ 2,4-Cl₂—Ph  48 C—Me CH(Et)CH₂CH₂NMe₂ 2,4-Cl₂—Ph  49^(o) C—Me NHCH(CH₂OMe)₂ 2,4,6-Me₃—Ph 125–127  50 C—Me NHCHPr₂ 2,4,6-Me₃—Ph  51 C—Me NEtBu 2,4,6-Me₃—Ph  52 C—Me NPr(CH₂-c-C₃H₅) 2,4,6-Me₃—Ph  53^(ae) C—Me N(CH₂CH₂OMe)₂ 2,4,6-Me₃—Ph 123–124  54 C—Me NH-3-heptyl 2,4,6-Me₃—Ph  55^(ac) C—Me NHCH(Et)CH₂OMe 2,4,6-Me₃—Ph 145–146  56^(ah) C—Me NEt₂ 2,4,6-Me₃—Ph 88–90  57^(ai) C—Me NHCH(CH₂OEt)₂ 2,4,6-Me₃—Ph 132–134  58^(ad) C—Me NH-3-pentyl 2,4,6-Me₃—Ph 134–135  59 C—Me NMePh 2,4,6-Me₃—Ph  60 C—Me NPr₂ 2,4,6-Me₃—Ph  61 C—Me NH-3-hexyl 2,4,6-Me₃—Ph  62 C—Me morpholino 2,4,6-Me₃—Ph  63 C—Me N(CH₂Ph)CH₂CH₂OMe 2,4,6-Me₃—Ph  64 C—Me NHCH(CH₂Ph)CH₂OMe 2,4,6-Me₃—Ph  65 C—Me NH-4-tetrahydropyranyl 2,4,6-Me₃—Ph  66 C—Me NH-cyclopentyl 2,4,6-Me₃—Ph  67 C—Me 1,2,3,4-tetrahydro- 2,4,6-Me₃—Ph isoquinolinyl  68 C—Me CH₂-(1,2,3,4-tetrahydro- 2,4,6-Me₃—Ph isoquinolinyl)  69 C—Me OEt 2,4,6-Me₃—Ph  70 C—Me OCH(Et)CH₂OMe 2,4,6-Me₃—Ph  71 C—Me OCH₂Ph 2,4,6-Me₃—Ph  72 C—Me O-3-pentyl 2,4,6-Me₃—Ph  73 C—Me SEt 2,4,6-Me₃—Ph  74 C—Me S(O)Et 2,4,6-Me₃—Ph  75 C—Me SO₂Et 2,4,6-Me₃—Ph  76 C—Me CH(CO₂Et)2 2,4,6-Me₃—Ph  77 C—Me C(Et)(CO₂Et)₂ 2,4,6-Me₃—Ph  78 C—Me CH(Et)CH₂OH 2,4,6-Me₃—Ph  79 C—Me CH(Et)CH₂OMe 2,4,6-Me₃—Ph  80 C—Me CONMe₂ 2,4,6-Me₃—Ph  81 C—Me COCH₃ 2,4,6-Me₃—Ph  82 C—Me CH(OH)CH₃ 2,4,6-Me₃—Ph  83 C—Me C(OH)Ph-3-pyridyl 2,4,6-Me₃—Ph  84 C—Me Ph 2,4,6-Me₃—Ph  85 C—Me 2-CF₃—Ph 2,4,6-Me₃—Ph  86 C—Me 2-Ph-Ph 2,4,6-Me₃—Ph  87 C—Me 3-pentyl 2,4,6-Me₃—Ph  88 C—Me cyclobutyl 2,4,6-Me₃—Ph  89 C—Me 3-pyridyl 2,4,6-Me₃—Ph  90 C—Me CH(Et)CH₂CONMe₂ 2,4,6-Me₃—Ph  91 C—Me CH(Et)CH₂CH₂NMe₂ 2,4,6-Me₃—Ph  92^(p) C—Me NHCH(CH₂OMe)₂ 2,4-Me₂—Ph 44–45  93^(q) C—Me N(CH₂CH₂OMe)₂ 2,4-Me₂—Ph oil  94^(r) C—Me NHCH(Et)CH₂OMe 2,4-Me₂—Ph 102–104  95^(s) C—Me NH-3-pentyl 2,4-Me₂—Ph 102–104  96^(t) C—Me NEt₂ 2,4-Me₂—Ph oil  97^(u) C—Me N(CH₂CN)₂ 2,4-Me₂—Ph 148–150  98^(v) C—Me NHCH(Me)CH₂OMe 2,4-Me₂—Ph 102–104  99^(w) C—Me OCH(Et)CH₂OMe 2,4-Me₂—Ph oil 100^(x) C—Me NPr-c-C₃H₅ 2,4-Me₂—Ph oil 101^(y) C—Me NHCH(Me)CH₂NMe₂ 2,4-Me₂—Ph 47–48 202^(z) C—Me N(c-C₃H₅)CH₂CH₂CN 2,4-Me₂—Ph 117–118 103^(aa) C—Me N(Pr)CH₂CH₂CN 2,4-Me₂—Ph oil 104^(ab) C—Me N(Bu)CH₂CH₂CN 2,4-Me₂—Ph oil 105 C—Me NHCHPr₂ 2,4-Me₂—Ph 106 C—Me NEtBu 2,4-Me₂—Ph 107 C—Me NPr(CH₂-c-C₃H₅) 2,4-Me₂—Ph 108 C—Me NH-3-heptyl 2,4-Me₂—Ph 109 C—Me NEt₂ 2,4-Me₂—Ph 110 C—Me NHCH(CH₂OEt)₂ 2,4-Me₂—Ph 111 C—Me NH-3-pentyl 2,4-Me₂—Ph 112 C—Me NMePh 2,4-Me₂—Ph 113 C—Me NPr₂ 2,4-Me₂—Ph 114 C—Me NH-3-hexyl 2,4-Me₂—Ph 115 C—Me morpholino 2,4-Me₂—Ph 116 C—Me N(CH₂Ph)CH₂CH₂OMe 2,4-Me₂—Ph 117 C—Me NHCH(CH₂Ph)CH₂OMe 2,4-Me₂—Ph 118 C—Me NH-4-tetrahydropyranyl 2,4-Me₂—Ph 119 C—Me NH-cyclopentyl 2,4-Me₂—Ph 120 C—Me 1,2,3,4-tetrahydro- 2,4-Me₂—Ph isoquinolinyl 121 C—Me CH₂-(1,2,3,4-tetrahydro- 2,4-Me₂—Ph isoquinolinyl) 122 C—Me OEt 2,4-Me₂—Ph 123 C—Me OCH(Et)CH₂OMe 2,4-Me₂—Ph 124 C—Me OCH₂Ph 2,4-Me₂—Ph 125 C—Me O-3-pentyl 2,4-Me₂—Ph 126 C—Me SEt 2,4-Me₂—Ph 127 C—Me S(O)Et 2,4-Me₂—Ph 128 C—Me SO₂Et 2,4-Me₂—Ph  3 C—Me CH(CO₂Et)₂ 2,4-Me₂—Ph 50–52 129 C—Me C(Et)(CO₂Et)₂ 2,4-Me₂—Ph 130 C—Me CH(Et)CH₂OH 2,4-Me₂—Ph 131 C—Me CH(Et)CH₂OMe 2,4-Me₂—Ph 132 C—Me CH(Et)CH₂OEt 2,4-Me₂—Ph 133 C—Me CONMe₂ 2,4-Me₂—Ph 134 C—Me COCH₃ 2,4-Me₂—Ph 135 C—Me CH(OH)CH₃ 2,4-Me₂—Ph 136 C—Me C(OH)Ph-3-pyridyl 2,4-Me₂—Ph 137 C—Me Ph 2,4-Me₂—Ph 138 C—Me 2-CF₃—Ph 2,4-Me₂—Ph 139 C—Me 2-Ph—Ph 2,4-Me₂—Ph 140 C—Me 3-pentyl 2,4-Me₂—Ph 141 C—Me cyclobutyl 2,4-Me₂—Ph 142 C—Me 3-pyridyl 2,4-Me₂—Ph 143 C—Me CH(Et)CH₂CONMe₂ 2,4-Me₂—Ph 144 C—Me CH(Et)CH₂CH₂NMe₂ 2,4-Me₂—Ph 145^(bc) C—Me NHCH(CH₂OMe)₂ 2-Me-4-MeO—Ph 45–46 146^(bd) C—Me N(CH₂CH₂OMe)₂ 2-Me-4-MeO—Ph oil 147^(be) C—Me NHCH(Et)CH₂OMe 2-Me-4-MeO—Ph 86–88 148^(bf) C—Me N(Pr)CH₂CH₂CN 2-Me-4-MeO—Ph oil 149 C—Me OCH(Et)CH₂OMe 2-Me-4-MeO—Ph 150^(af) C—Me NHCH(CH₂OMe)₂ 2-Br-4-MeO—Ph 88–90 151^(al) C—Me N(CH₂CH₂OMe)₂ 2-Br-4-MeO—Ph oil 152^(ag) C—Me NHCH(Et)CH₂OMe 2-Br-4-MeO—Ph 95–97 153 C—Me N(Pr)CH₂CH₂CN 2-Br-4-MeO—Ph 154 C—Me OCH(Et)CH₂OMe 2-Br-4-MeO—Ph 155 C—Me NHCH(CH₂OMe)₂ 2-Me-4-NMe₂—Ph 156 C—Me N(CH₂CH₂OMe)₂ 2-Me-4-NMe₂—Ph oil 157 C—Me NHCH(Et)CH₂OMe 2-Me-4-NMe₂—Ph 158 C—Me N(Pr)CH₂CH₂CN 2-Me-4-NMe₂—Ph 159 C—Me OCH(Et)CH₂OMe 2-Me-4-NMe₂—Ph 160 C—Me NHCH(CH₂OMe)₂ 2-Br-4-NMe₂—Ph 161 C—Me N(CH₂CH₂OMe)₂ 2-Br-4-NMe₂—Ph 162 C—Me NHCH(Et)CH₂OMe 2-Br-4-NMe₂—Ph 163 C—Me N(Pr)CH₂CH₂CN 2-Br-4-NMe₂—Ph 164 C—Me OCH(Et)CH₂OMe 2-Br-4-NMe₂—Ph 165 C—Me NHCH(CH₂OMe)₂ 2-Br-4-i-Pr—Ph 166 C—Me N(CH₂CH₂OMe)₂ 2-Br-4-i-Pr—Ph 167 C—Me NHCH(Et)CH₂OMe 2-Br-4-i-Pr—Ph 168 C—Me N(Pr)CH₂CH₂CN 2-Br-4-i-Pr—Ph 169 C—Me OCH(Et)CH₂OMe 2-Br-4-i-Pr—Ph 170 C—Me NHCH(CH₂OMe)₂ 2-Br-4-Me—Ph 171 C—Me N(CH₂CH₂OMe)₂ 2-Br-4-Me—Ph 172 C—Me NHCH(Et)CH₂OMe 2-Br-4-Me—Ph 173 C—Me N(Pr)CH₂CH₂CN 2-Br-4-Me—Ph 174 C—Me OCH(Et)CH₂OMe 2-Br-4-Me—Ph 175^(ar) C—Me NHCH(CH₂OMe)₂ 2-Me-4-Br—Ph 108–109 176 C—Me N(CH₂CH₂OMe)₂ 2-Me-4-Br—Ph 177 C—Me NHCH(Et)CH₂OMe 2-Me-4-Br—Ph 178 C—Me N(Pr)CH₂CH₂CN 2-Me-4-Br—Ph 179 C—Me OCH(Et)CH₂OMe 2-Me-4-Br—Ph 180 C—Me NHCH(CH₂OMe)₂ 2-Cl-4,6-Me₂—Ph 181 C—Me N(CH₂CH₂OMe)₂ 2-Cl-4,6-Me₂—Ph 182 C—Me NHCH(CH₂OMe)₂ 4-Br-2,6-(Me)₂—Ph 183 C—Me N(CH₂CH₂OMe)₂ 4-Br-2,6-(Me)₂—Ph 184 C—Me NHCH(CH₂OMe)₂ 4-i-Pr-2-SMe—Ph 185 C—Me N(CH₂CH₂OMe)₂ 4-i-Pr-2-SMe—Ph 186 C—Me NHCH(CH₂OMe)₂ 2-Br-4-CF₃—Ph 187 C—Me N(CH₂CH₂OMe)₂ 2-Br-4-CF₃—Ph 188 C—Me NHCH(CH₂OMe)₂ 2-Br-4,6-(MeO)₂—Ph 189 C—Me N(CH₂CH₂OMe)₂ 2-Br-4,6-(MeO)₂—Ph 190 C—Me NHCH(CH₂OMe)₂ 2-Cl-4,6-(MeO)₂—Ph 191 C—Me N(CH₂CH₂OMe)₂ 2-Cl-4,6-(MeO)₂—Ph 192 C—Me NHCH(CH₂OMe)₂ 2,6-(Me)₂-4-SMe—Ph 193 C—Me N(CH₂CH₂OMe)₂ 2,6-(Me)₂-4-SMe—Ph 194 C—Me NHCH(CH₂OMe)₂ 4-(COMe)-2-Br—Ph 195 C—Me N(CH₂CH₂OMe)₂ 4-(COMe)-2-Br—Ph 196 C—Me NHCH(CH₂OMe)₂ 2,4,6-Me₃-pyrid-3-yl 197 C—Me N(CH₂CH₂OMe)₂ 2,4,6-Me₃-pyrid-3-yl 198 C—Me NHCH(CH₂OMe)₂ 2,4-(Br)₂—Ph 199 C—Me N(CH₂CH₂OMe)₂ 2,4-(Br)₂—Ph 200 C—Me NHCH(CH₂OMe)₂ 4-i-Pr-2-SMe—Ph 201 C—Me N(CH₂CH₂OMe)₂ 4-i-Pr-2-SMe—Ph 202 C—Me NHCH(CH₂OMe)₂ 4-i-Pr-2-SO₂Me—Ph 203 C—Me N(CH₂CH₂OMe)₂ 4-i-Pr-2-SO₂Me—Ph 204 C—Me NHCH(CH₂OMe)₂ 2,6-(Me)₂-4-SMe—Ph 205 C—Me N(CH₂CH₂OMe)₂ 2,6-(Me)₂-4-SMe—Ph 206 C—Me NHCH(CH₂OMe)₂ 2,6-(Me)₂-4-SO₂Me—Ph 207 C—Me N(CH₂CH₂OMe)₂ 2,6-(Me)₂-4-SO₂Me—Ph 208 C—Me NHCH(CH₂OMe)₂ 2-I-4-i-Pr—Ph 209 C—Me N(CH₂CH₂OMe)₂ 2-I-4-i-Pr—Ph 210 C—Me NHCH(CH₂OMe)₂ 2-Br-4-N(Me)₂-6-MeO—Ph 211 C—Me N(CH₂CH₂OMe)₂ 2-Br-4-N(Me)₂-6-MeO—Ph 212 C—Me NHCH(CH₂OMe)₂ 2,4-[SMe]2-Ph 213 C—Me N(CH₂CH₂OMe)₂ 2,4-[SMe]2-Ph 214 C—Me NHCH(CH₂OMe)₂ 2,4-[SO₂Me]2-Ph 215 C—Me N(CH₂CH₂OMe)₂ 2,4-[SO₂Me 2-Ph 216 C—Me NHCH(CH₂OMe)₂ 4-i-Pr-2-SMe—Ph 217 C—Me N(CH₂CH₂OMe)₂ 4-i-Pr-2-SMe—Ph 218 C—Me NHCH(CH₂OMe)₂ 4-i-Pr-2-SO₂Me—Ph 219 C—Me N(CH₂CH₂OMe)₂ 4-i-Pr-2-SO₂Me—Ph 220 C—Me NHCH(CH₂OMe)₂ 2-N(Me)₂-4-Me—Ph 221 C—Me N(CH₂CH₂OMe)₂ 2-N(Me)₂-4-Me—Ph 222 C—Me NHCH(CH₂OMe)₂ 2-MeS-4,6-(Me)₂—Ph 223 C—Me N(CH₂CH₂OMe)₂ 2-MeS-4,6-(Me)₂—Ph 224 C—Me NHCH(CH₂OMe)₂ 2-(CH₃CO)-4,6-(Me)₂—Ph 225 C—Me N(CH₂CH₂OMe)₂ 2-(CH₃CO)-4,6-(Me)₂—Ph 226 H NHCH(CH₂OMe)₂ 2,4-Me₂—Ph 227 H NHCH(CH₂OMe)₂ 2,4-Me₂—Ph 228 CF3 N(CH₂CH₂OMe)₂ 2,4-Me₂—Ph 229 CF3 N(CH₂CH₂OMe)₂ 2,4-Me₂—Ph 230 N NHCH(CH₂OMe)₂ 2,4,6-Me₃—Ph 231 N NHCHPr₂ 2,4,6-Me₃—Ph 232 N NEtBu 2,4,6-Me₃—Ph 233 N NPr(CH₂-c-C₃H₅) 2,4,6-Me₃—Ph 234 N N(CH₂CH₂OMe)₂ 2,4,6-Me₃—Ph 235 N NH-3-heptyl 2,4,6-Me₃—Ph 236 N NHCH(Et)CH₂OMe 2,4,6-Me₃—Ph 237 N NEt₂ 2,4,6-Me₃—Ph 238 N NHCH(CH₂OEt)₂ 2,4,6-Me₃—Ph 239 N NH-3-pentyl 2,4,6-Me₃—Ph 240 N NMePh 2,4,6-Me₃—Ph 241 N NPr₂ 2,4,6-Me₃—Ph 242 N NH-3-hexyl 2,4,6-Me₃—Ph 243 N morpholino 2,4,6-Me₃—Ph 244 N N(CH₂Ph)CH₂CH₂OMe 2,4,6-Me₃—Ph 245 N NHCH (CH₂Ph)CH₂OMe 2,4,6-Me₃—Ph 246 N NH-4-tetrahydropyranyl 2,4,6-Me₃—Ph 247 N NH-cyclopentyl 2,4,6-Me₃—Ph 248 N 1,2,3,4-tetrahydro- 2,4,6-Me₃—Ph isoquinolinyl 249 N CH₂-(1,2,3,4-tetrahydro- 2,4,6-Me₃—Ph isoquinolinyl) 250 N OEt 2,4,6-Me₃—Ph 251 N OCH(Et)CH₂OMe 2,4,6-Me₃—Ph 252 N OCH₂Ph 2,4,6-Me₃—Ph 253 N O-3-pentyl 2,4,6-Me₃—Ph 254 N SEt 2,4,6-Me₃—Ph 255 N S(O)Et 2,4,6-Me₃—Ph 256 N SO₂Et 2,4,6-Me₃—Ph 257 N CH(CO₂Et)₂ 2,4,6-Me₃—Ph 258 N C(Et)(CO₂Et)₂ 2,4,6-Me₃—Ph 259 N CH(Et)CH₂OH 2,4,6-Me₃—Ph 260 N CH(Et)CH₂OMe 2,4,6-Me₃—Ph 261 N CONMe₂ 2,4,6-Me₃—Ph 262 N COCH₃ 2,4,6-Me₃—Ph 263 N CH(OH)CH₃ 2,4,6-Me₃—Ph 264 N C(OH)Ph-3-pyridyl 2,4,6-Me₃—Ph 265 N Ph 2,4,6-Me₃—Ph 266 N 2-CF₃—Ph 2,4,6-Me₃—Ph 267 N 2-Ph—Ph 2,4,6-Me₃—Ph 268 N 3-pentyl 2,4,6-Me₃—Ph 269 N cyclobutyl 2,4,6-Me₃—Ph 270 N 3-pyridyl 2,4,6-Me₃—Ph 271 N CH(Et)CH₂CONMe₂ 2,4,6-Me₃—Ph 272 N CH(Et)CH₂CH₂NMe₂ 2,4,6-Me₃—Ph 273 N NHCH(CH₂OMe)₂ 2,4-Me₂—Ph 274 N NHCHPr₂ 2,4-Me₂—Ph 275 N NEtBu 2,4-Me₂—Ph 276 N NPr(CH₂-c-C₃H₅) 2,4-Me₂—Ph 277 N N(CH₂CH₂OMe)₂ 2,4-Me₂—Ph 278 N NH-3-heptyl 2,4-Me₂—Ph 279 N NHCH(Et)CH₂OMe 2,4-Me₂—Ph 280 N NEt₂ 2,4-Me₂—Ph 281 N NHCH(CH₂OEt)₂ 2,4-Me₂—Ph 282 N NH-3-pentyl 2,4-Me₂—Ph 283 N NMePh 2,4-Me₂—Ph 284 N NPr₂ 2,4-Me₂—Ph 285 N NH-3-hexyl 2,4-Me₂—Ph 286 N morpholino 2,4-Me₂—Ph 287 N N(CH₂Ph)CH₂CH₂OMe 2,4-Me₂—Ph 288 N NHCH(CH₂Ph)CH₂OMe 2,4-Me₂—Ph 289 N NH-4-tetrahydropyranyl 2,4-Me₂—Ph 290 N NH-cyclopentyl 2,4-Me₂—Ph 291 N 1,2,3,4-tetrahydro- 2,4-Me₂—Ph isoquinolinyl 292 N CH₂-(1,2,3,4-tetrahydro- 2,4-Me₂—Ph isoquinolinyl) 293 N OEt 2,4-Me₂—Ph 294 N OCH(Et)CH₂OMe 2,4-Me₂—Ph 295 N OCH₂Ph 2,4-Me₂—Ph 296 N O-3-pentyl 2,4-Me₂—Ph 297 N SEt 2,4-Me₂—Ph 298 N S(O)Et 2,4-Me₂—Ph 299 N SO₂Et 2,4-Me₂—Ph 300 N CH(CO₂Et)₂ 2,4-Me₂—Ph 301 N C(Et)(CO₂Et)₂ 2,4-Me₂—Ph 302 N CH(Et)CH₂OH 2,4-Me₂—Ph 303 N CH(Et)CH₂OMe 2,4-Me₂—Ph 304 N CONMe₂ 2,4-Me₂—Ph 305 N COCH₃ 2,4-Me₂—Ph 306 N CH(OH)CH₃ 2,4-Me₂—Ph 307 N C(OH)Ph-3-pyridyl 2,4-Me₂—Ph 308 N Ph 2,4-Me₂—Ph 309 N 2-CF₃—Ph 2,4-Me₂—Ph 310 N 2-Ph—Ph 2,4-Me₂—Ph 311 N 3-pentyl 2,4-Me₂—Ph 312 N cyclobutyl 2,4-Me₂—Ph 313 N 3-pyridyl 2,4-Me₂—Ph 314 N CH(Et)CH₂CONMe₂ 2,4-Me₂—Ph 315 N CH(Et)CH₂CH₂NMe₂ 2,4-Me₂—Ph 316^(an) C—Me NEt₂ 2-Br-4-MeO—Ph oil 317^(am) C—Me NH-3-pentyl 2-Br-4-MeO—Ph oil 318^(aj) C—Me NHCH(CH₂CH₂OMe)CH₂OMe 2,4,6-Me₃—Ph 101–103 319^(ao) C—Me NH(c-C₃H₅) 2,4-Me₂—Ph oil 320^(ak) C—Me morpholino 2,4,6-Me₃—Ph 139–141 321^(ap) C—Me NHCH(CH₂OMe)₂ 2-CN-4-Me—Ph 152–153 322^(aq) C—Me N(c-C₃H₅)CH₂CH₂CN 2,4,6-Me₃—Ph 149–151 324^(as) C—Me NHCH(CH₂CH₂OMe)CH₂OMe 2-Me-4-Br—Ph 115–117 325^(at) C—Me NHCH(CH₂OMe)₂ 2,5-Me₂-4-MeO—Ph 55–57 326^(au) C—Me N(CH₂CH₂OMe)₂ 2,5-Me₂-4-MeO—Ph 72 327^(av) C—Me NH-3-pentyl 2,5-Me₂-4-MeO—Ph 45–47 328^(aw) C—Me NEt₂ 2,5-Me₂-4-MeO—Ph oil 329^(ax) C—Me NHCH(CH₂OMe)₂ 2-Cl-4-MePh 80–81 330^(ay) C—Me NCH(Et)CH₂OMe 2-Cl-4-MePh 77–79 331^(az) C—Me N(CH₂CH₂OMe)₂ 2-Cl-4-MePh oil 332^(ba) C—Me (S)-NHCH(CH₂CH₂OMe)CH₂OMe 2-Cl-4-MePh 139–140 333^(bb) C—Me N(c-C₃H₅)CH₂CH₂CN 2,5-Me₂-4-MeOPh 120–122 334^(bg) C—Me NEt₂ 2-Me-4-MeOPh oil 335^(bh) C—Me OEt 2-Me-4-MeOPh oil 336^(bi) C—Me (S)-NHCH(CH₂CH₂OMe)CH₂OMe 2-Me-4-MeOPh oil 337^(bj) C—Me N(c-C₃H₅)CH₂CH₂CN 2-Me-4-MeOPh 129 338^(bk) C—Me NHCH(CH₂CH₂OEt)₂ 2-Me-4-MeOPh amorph. 339 C—Me N(c-C₃H₅)CH₂CH₂CN 2,4-Cl₂—Ph 109–110 340 C—Me (S)-NHCH(CH₂CH₂OMe)CH₂OMe 2,4-Cl₂—Ph 93–94 341 C—Me NH-3-pentyl 2-Me-4-BrPh 118–119 342 C—Me N(CH₂CH₂OMe)₂ 2-Me-4-BrPh oil 343 C—Me NHCH(CH₂-iPr)CH₂OMe 2,4-Me₂—Ph oil 344 C—Me NHCH(Pr)CH₂OMe 2,4-Me₂—Ph 94–95 345 C—Me NHCH(Et)CH₂OEt 2,4-Me₂—Ph 76–77 346 C—Me NHCH(CH₂OMe)CH₂CH₂OMe 2-Me-4-Me₂NPh oil 347 C—Me NEt₂ 2-Me-4-ClPh oil 348 C—Me NH-3-pentyl 2-Me-4-ClPh 122–124 349 C—Me N(CH₂CH₂OMe)₂ 2-Me-4-ClPh oil 350 C—Me NHCH(CH₂OMe)₂ 2-Me-4-ClPh 122–123 351 C—Me NEt₂ 2-Me-4-ClPh oil 352 C—Me NEt₂ 2-Cl-4-MePh oil 353 C—Me NH-3-pentyl 2-Cl-4-MePh 120–121 354 C—Me NHCH(CH₂OMe)₂ 2-Cl-4-MeOPh 355^(bl) C—Me N(CH₂CH₂OMe)₂ 2-Cl-4-MeOPh oil 356^(bm) C—Me NHCH(Et)CH₂OMe 2-Cl-4-MeOPh 108–110 357^(bn) C—Me N(c-Pr)CH₂CH₂CN 2-Cl-4-MeOPh 127–129 358^(bo) C—Me NEt₂ 2-Cl-4-MeOPh oil 359^(bp) C—Me NH-3-pentyl 2-Cl-4-MeOPh 77–79 360 C—Me NHCH(Et)CH₂CH₂OMe 2-Cl-4-MeOPh 361 C—Me NHCH(Me)CH₂CH₂OMe 2-Cl-4-MeOPh 362 C—Me NHCH(Et)CH₂CH₂OMe 2-Br-4-MeOPh 363 C—Me NHCH(Me)CH₂CH₂OMe 2-Br-4-MeOPh 364 C—Me NHCH(Et)CH₂CH₂OMe 2-Me-4-MeOPh 365 C—Me NHCH(Me)CH₂CH₂OMe 2-Me-4-MeOPh 366 C—Me NHCH(CH₂OMe)₂ 2-Cl-4,5-(MeO)₂Ph 367 C—Me N(CH₂CH₂OMe)₂ 2-Cl-4,5-(MeO)₂Ph 368 C—Me NHCH(Et)CH₂OMe 2-Cl-4,5-(MeO)₂Ph 369 C—Me N(c-Pr)CH₂CH₂CN 2-Cl-4,5-(MeO)₂Ph 370 C—Me NEt₂ 2-Cl-4,5-(MeO)₂Ph 371 C—Me NH-3-pentyl 2-Cl-4,5-(MeO)₂Ph 372 C—Me NHCH(Et)CH₂CH₂OMe 2-Cl-4,5-(MeO)₂Ph 373 C—Me NHCH(Me)CH₂CH₂OMe 2-Cl-4,5-(MeO)₂Ph 374^(bq) C—Me NHCH(CH₂OMe)₂ 2-Br-4,5-(MeO)₂Ph 137–138 375 C—Me N(CH₂CH₂OMe)₂ 2-Br-4,5-(MeO)₂Ph 376^(br) C—Me NHCH(Et)CH₂OMe 2-Br-4,5-(MeO)₂Ph 147–148 377 C—Me N(c-Pr)CH₂CH₂CN 2-Br-4,5-(MeO)₂Ph 378^(bs) C—Me NEt₂ 2-Br-4,5-(MeO)₂Ph 52–58 379 C—Me NH-3-pentyl 2-Br-4,5-(MeO)₂Ph 380 C—Me NHCH(Et)CH₂CH₂OMe 2-Br-4,5-(MeO)₂Ph 381 C—Me NHCH(Me)CH₂CH₂OMe 2-Br-4,5-(MeO)₂Ph 382 C—Me NHCH(CH₂OMe)₂ 2-Cl-4,6-(MeO)₂Ph 383 C—Me N(CH₂CH₂OMe)₂ 2-Cl-4,6-(MeO)₂Ph 384 C—Me NHCH(Et)CH₂OMe 2-Cl-4,6-(MeO)₂Ph 385 C—Me N(c-Pr)CH₂CH₂CN 2-Cl-4,6-(MeO)₂Ph 386 C—Me NEt₂ 2-Cl-4,6-(MeO)₂Ph 387 C—Me NH-3-pentyl 2-Cl-4,6-(MeO)₂Ph 388 C—Me NHCH(Et)CH₂CH₂OMe 2-Cl-4,6-(MeO)₂Ph 389 C—Me NHCH(Me)CH₂CH₂OMe 2-Cl-4,6-(MeO)₂Ph 390 C—Me NHCH(CH₂OMe)₂ 2-Me-4,6-(MeO)₂Ph 391 C—Me N(CH₂CH₂OMe)₂ 2-Me-4,6-(MeO)₂Ph 392 C—Me NHCH(Et)CH₂OMe 2-Me-4,6-(MeO)₂Ph 393 C—Me N(c-Pr)CH₂CH₂CN 2-Me-4,6-(MeO)₂Ph 395 C—Me NEt₂ 2-Me-4,6-(MeO)₂Ph 396 C—Me NH-3-pentyl 2-Me-4,6-(MeO)₂Ph 397 C—Me NHCH(Et)CH₂CH₂OMe 2-Me-4,6-(MeO)₂Ph 398 C—Me NHCH(Me)CH₂CH₂OMe 2-Me-4,6-(MeO)₂Ph 399 C—Me N(c-Pr)CH₂CH₂CN 2-Br-4,6-(MeO)₂Ph 400 C—Me NEt₂ 2-Br-4,6-(MeO)₂Ph 401 C—Me NH-3-pentyl 2-Br-4,6-(MeO)₂Ph 402 C—Me NHCH(Et)CH₂CH₂OMe 2-Br-4,6-(MeO)₂Ph 403 C—Me NHCH(Me)CH₂CH₂OMe 2-Br-4,6-(MeO)₂Ph 404 C—Me NHCH(Et)CH₂CH₂OMe 2-Me-4-MeOPh 405 C—Me NHCH(Me)CH₂CH₂OMe 2-Me-4-MeOPh 406 C—Me NHCH(CH₂OMe)₂ 2-MeO-4-MePh 407 C—Me N(CH₂CH₂OMe)₂ 2-MeO-4-MePh 408 C—Me NHCH(Et)CH₂OMe 2-MeO-4-MePh 409 C—Me N(c-Pr)CH₂CH₂CN 2-MeO-4-MePh 410 C—Me NEt₂ 2-MeO-4-MePh 411 C—Me NH-3-pentyl 2-MeO-4-MePh 412 C—Me NHCH(Et)CH₂CH₂OMe 2-MeO-4-MePh 413 C—Me NHCH(Me)CH₂CH₂OMe 2-MeO-4-MePh 414 C—Me NHCH(CH₂OMe)₂ 2-MeO-4-MePh 415 C—Me N(CH₂CH₂OMe)₂ 2-MeO-4-MePh 416 C—Me NHCH(Et)CH₂OMe 2-MeO-4-MePh 417 C—Me N(c-Pr)CH₂CH₂CN 2-MeO-4-MePh 418 C—Me NEt₂ 2-MeO-4-MePh 419 C—Me NH-3-pentyl 2-MeO-4-MePh 420 C—Me NHCH(Et)CH₂CH₂OMe 2-MeO-4-MePh 421 C—Me NHCH(Me)CH₂CH₂OMe 2-MeO-4-MePh 423^(bt) C—Me NHCH(CH₂OMe)₂ 2-MeO-4-ClPh oil 424 C—Me N(CH₂CH₂OMe)₂ 2-MeO-4-ClPh 425 C—Me NHCH(Et)CH₂OMe 2-MeO-4-ClPh 426 C—Me N(c-Pr)CH₂CH₂CN 2-MeO-4-ClPh 427 C—Me NEt₂ 2-MeO-4-ClPh 428 C—Me NH-3-pentyl 2-MeO-4-ClPh 429 C—Me NHCH(Et)CH₂CH₂OMe 2-MeO-4-ClPh 430 C—Me NHCH(Me)CH₂CH₂OMe 2-Me0-4-ClPh

Notes for Table 1:

a) Analysis Calcd: C, 52.69, H, 5.17, N, 17.07, Cl, 17.28; Found: C, 52.82, H, 5.06, N, 16.77, Cl, 17.50.

b) CI-HRMS: Calcd: 406.1565, Found: 405.1573 (M+H); Analysis Calcd: C, 59.11; H, 6.20; N, 17.23; Cl: 17.45; Found: C, 59.93; H, 6.34; N, 16.50; Cl: 16.95; NMR (CDCl₃, 300 MHz): 0.95 (t, J=8, 4H), 1.30–1.40 (m, 4H), 1.50–1.75 (m, 4H), 2.35 (s, 3H), 2.48 (s, 3H), 4.30–4.45 (m, 1H), 6.15 (d, J=8, 1H), 7.30 (s, 2H), 7.50 (s, 1H)

c) CI-HRMS: Calcd: 392.1409, Found: 392.1388 (M+H); NMR (CDCl₃, 300 MHz): 1.00 (t, J=8, 3H), 1.35 (t, J=8, 3H), 1.41 (q, J=8, 2H), 1.65–1.85 (m, 2H), 2.30 (s, 3H), 2.40 (s, 3H), 3.85–4.20 (m, 4H), 7.30 (s, 2H), 7.50 (s, 1H).

d) CI-HRMS: Calcd: 404.1409, Found: 404.1408 (M+H); NMR(CDCl₃, 300 MHz): 0.35–0.45 (m, 2H), 0.52–0.62 (m, 2H), 0.98 (t, J=8, 3H), 1.70–1.90 (m, 2H), 2.30 (s, 3H), 2.40 (s, 3H), 3.85–4.02 (m, 2H), 4.02–4.20 (m, 2H), 7.30 (s, 2H), 7.50 (s, 1H).

e) CI-HRMS: Calcd: 424.1307, Found: 424.1307 (M+H): NMR (CDCl₃, 300 MHz): 2.28 (s, 3H), 2.40 (s, 3H), 3.40 (s, 6H), 3.75 (t, J=8, 4H), 4.20–4.45 (m, 4H), 7.30 (s, 2H), 7.50 (s, 1H).

f) CI-HRMS: Calcd: 406.1565, Found: 406.1578 (M+H); NMR (CDCl₃, 300 MHz): 0.90 (t, J=8, 3H), 1.00 (t, J=8, 3H), 1.28–1.45 (m, 4H), 1.50–1.80 (m, 4H), 2.35 (s, 3H), 2.50 (s, 3H), 4.20–4.35 (m, 1H), 6.10–6.23 (m, 1H), 7.30 (s, 2H), 7.50 (s, 1H).

g) CI-HRMS: Calcd: 394.1201, Found: 394.1209 (M+H); NMR (CDCl₃, 300 MHz): 1.02 (t, J=8, 3H), 1.65–1.90 (m, 2H), 2.35 (s, 3H), 2.48 (s, 3H), 3.40 (s, 3H), 3.50–3.60 (m, 2H), 4.35–4.45 (brs, 1H), 6.50–6.60 (m, 1H), 7.30 (s, 2H), 7.50 (s, 1H).

h) CI-HRMS: Calcd: 364.1096, Found: 364.1093 (M+H); Analysis: Calcd: C, 56.05; H, 5.27; N, 19.23; Cl: 19.46; Found: C, 55.96; H, 5.24; N, 18.93; Cl: 19.25; NMR (CDCl₃, 300 MHz): 1.35 (t, J=8, 6H), 2.30 (3, 3H), 2.40 (s, 3H), 3.95–4.15 (m, 4H), 7.30 (s, 2H), 7.50 (d, J=1, 1H).

i) CI-HRMS: Calcd: 438.1464, Found: 438.1454 (M+H); NMR (CDCl₃, 300 MHz): 1.22 (t, J=8, 6H), 2.35 (s, 3H), 2.47 (s, 3H), 3.39 (q, J=8, 4H), 3.65 (dd, J=8, 1, 2H), 3.73 (dd, J=8, 1, 2H), 4.55–4.65 (m, 1H), 6.75 (d, J=8, 1H), 7.30 (d, J=1, 2H), 7.50 (s, 1H).

j) CI-HRMS: Calcd: 378.1252, Found: 378.1249 (M+H); Analysis: Calcd: C, 57.15; H, 5.61; N, 18.51; Cl: 18.74; Found: C, 57.56; H, 5.65; N, 18.35; Cl: 18.45; NMR (CDCl₃, 300 MHz): 1.00 (t, J=8, 6H), 1.55–1.70 (m, 2H), 1.70–1.85 (m, 2H), 2.35 (s, 3H), 2.50 (s, 3H), 4.15–4.25 (m, 1H), 6.18 (d, J=8, 1H), 7.30 (s, 2H), 7.50 (s, 1H).

k) CI-HRMS: Calcd: 398.0939, Found: 398.0922 (M+H); Analysis: Calcd: C, 60.31; H, 4.30; N, 17.58; Cl: 17.80; Found: C, 60.29; H, 4.59; N, 17.09; Cl: 17.57; NMR (CDCl₃, 300 MHz): 2.05 (s, 3H), 2.50 (s, 3H), 3.78 (s, 3H), 7.20–7.45 (m, 7H), 7.50 (d, J=1, 1H).

l) CI-HRMS: Calcd: 392.1409, Found: 392.1391 (M+H); NMR (CDCl₃, 300 MHz): 0.98 (t, J=8, 6H), 1.70–1.85 (m, 4H), 2.30 (s, 3H), 2.40 (s, 3H), 3.80–4.10 (m, 4H), 7.30 (s, 2H), 7.50 (d, J=1, 1H).

m) CI-HRMS: Calcd: 392.1409, Found: 392.1415 (M+H); Analysis: Calcd: C, 58.17; H, 5.92; N, 17.85; Cl: 18.07; Found: C, 58.41; H, 5.85: N, 18.10; Cl: 17.75; NMR (CDCl₃, 300 MHz): 0.90–1.05 (m, 6H), 1.35–1.55 (m, 2H), 1.55–1.85 (m, 4H), 2.35 (s, 3H), 2.48 (s, 3H), 4.20–4.35 (m, 1H), 6.15 (d, J=8, 1H), 7.30 (s, 2H), 7.50 (d, J=1, 1H).

n) CI-HRMS: Calcd: 337.0623, Found: 337.0689 (M+H); Analysis: Calcd: C, 53.43; H, 4.18; N, 16.62; Cl: 21.03, Found: C, 53.56; H, 4.33; N, 16.56; Cl: 20.75; NMR (CDCl₃, 300 MHz): 1.60 (t, J=8, 3H), 2.40 (s, 3H), 2.55 (s, 3H), 4.80 (q, J=8, 2H), 7.30 (d, J=8, 1H), 7.35 (dd, J=8, 1, 1H), 7.55 (d, J=1, 1H)

o) CI-HRMS: Calcd: 383.2321, Found: 383.2309 (M+H); NMR (CDCl₃, 300 MHz): 2.00 (s, 6H), 2.20 (s, 3H), 2.30 (s, 3H), 2.45 (s, 3H), 3.45 (s, 6H), 3.61 (dd, J=8, 8, 2H), 3.70 (dd, J=8, 8, 2H), 4.60–4.70 (m, 1H), 6.70 (d, J=8, 1H), 6.94 (s, 2H).

p) CI-HRMS: Calcd: 370.2243, Found: 370.2246 (M+H); Analysis: Calcd: C, 65.02; H, 7.38; N, 18.96; Found: C, 65.22; H, 7.39; N, 18.71; NMR (CDCl₃, 300 MHz): 2.18 (s, 3H), 2.30 (s, 3H), 2.45 (s, 3H), 3.45 (s, 6H), 3.60 (dd, J=8, 8, 2H), 3.69 (dd, J=8, 8, 2H), 4.60–4.70 (m, 1H), 6.70 (d, J=8, 1H), 7.05 (d, J=8, 1H), 7.07 (d, J=8, 1H), 7.10 (s, 1H).

q) CI-HRMS: Calcd: 384.2400, Found: 384.2393 (M+H); NMR (CDCl₃, 300 MHz): 2.16 (s, 3H), 2.25 (s, 3H), 2.35 (s, 3H), 2.39 (s, 3H), 3.40 (s, 6H), 3.77 (t, J=8, 4H), 4.20–4.45 (m, 4H), 7.02 (d, J=8, 1H) 7.05 (s, 1H), 7.10 (d, J=7, 1H).

r) CI-HRMS: Calcd: 354.2294, Found: 354.2271 (M+H); Analysis: Calcd: C, 67.96; H, 7.71; N, 19.81; Found: C, 67.56; H, 7.37; N, 19.60; NMR (CDCl₃, 300 MHz): 1.03 (t, J=8, 3H), 1.65–1.88 (m, 2H), 2.17 (s, 3H), 2.30 (s, 3H), 2.35 (s, 3H), 2.45 (s, 3H), 3.40 (s, 3H), 3.50–3.62 (m, 2H), 4.30–4.45 (m, 1H), 6.51 (d, J=8, 1H), 7.04 (d, J=8, 1H), 7.10 (d, J=8, 1H), 7.12 (s, 1H).

s) CI-HRMS: Calcd: 338.2345, Found: 338.2332 (M+H); Analysis: Calcd: C, 71.18; H, 8.06; N, 20.75; Found: C, 71.43; H, 7.80; N, 20.70; NMR (CDCl₃, 300 MHz): 1.00 (t, J=8, 6H), 1.55–1.70 (m, 2H), 1.70–1.85 (m, 2H), 2.19 (s, 3H), 2.30 (s, 3H), 2.35 (s, 3H), 2.46 (s, 3H), 4.15–4.26 (m, 1H), 6.17 (d, J=8, 1H), 7.06 (d, J=8, 1H), 7.10 (d, J=1, 1H), 7.13 (s, 1H).

t) CI-HRMS: Calcd: 324.2188, Found: 324.2188 (M+H); NMR (CDCl₃, 300 MHz): 1.25 (t, J=8, 6H), 2.16 (s, 3H), 2.28 (s, 3H), 2.35 (s, 3H), 2.40 (s, 3H), 3.95–4.20 (m, 4H), 7.05 (dd, J=8, 1, 1H), 7.07 (s, 1H), 7.10 (d, J=1, 1H)

u) CI-HRMS: Calcd: 346.1780, Found: 346.1785 (M+H); Analysis: Calcd: C, 66.07; H, 5.54; N, 28.39; Found: C, 66.07; H, 5.60; N, 27.81; NMR (CDCl₃, 300 MHz): 2.15 (s, 3H), 2.32 (s, 3H) 2.17 (s, 3H), 2.52 (s, 3H), 5.25–5.35 (m, 4H), 7.08 (s, 2H), 7.15 (s, 1H).

v) CI-HRMS: Calcd: 340.2137, Found: 340.2137 (M+H); Analysis: Calcd: C, 67.23; H, 7.42; N, 20.63; Found:C, 67.11; H, 7.39; N, 20.26; NMR (CDCl₃, 300 MHz): 1.40 (d, J=8, 3H), 2.16 (s, 3H), 2.32 (s, 3H), 2.35 (s, 3H), 2.47 (s, 3H), 3.42 (s, 3H), 3.50–3.60 (m, 2H), 4.50–4.15 (m, 1H), 6.56 (d, J=8, 1H), 7.00–7.15 (m, 3H).

w) CI-HRMS: Calcd: 355.2134, Found: 355.2134 (M+H); NMR (CDCl₃, 300 MHz): 1.05 (t, J=8, 3H), 1.85–2.00 (m, 2H), 2.17 (s, 3H), 2.36 (s, 6H), 2.50 (s, 3H), 3.41 (s, 3H), 3.45 (dd, J=8, 3, 1H), 3.82 (dd, J=8, 1, 1H), 5.70–5.80 (m, 1H), 7.00–7.20 (m, 3H).

x) CI-HRMS: Calcd: 364.2501, Found: 364.2501 (M+H); NMR (CDCl₃, 300 MHz): 0.35–0.43 (m, 2H), 0.50–0.60 (m, 2H), 0.98 (t, J=8, 3H), 1.20–1.30 (m, 1H), 1.72–1.90 (m, 2H), 2.18 (s, 3H) 2.28 (s, 3H), 2.35 (s, 3H), 2.40 (s, 3H), 3.88–4.03 (m, 2H), 4.03–4.20 (m, 2H), 7.00–7.15 (m, 3H).

y) CI-HRMS: Calcd: 353.2454, Found: 353.2454 (M+H); Analysis: Calcd: C, 68.15; H, 8.02; N, 23.84; Found: C, 67.43; H, 7.81; N, 23.45; NMR (CDCl₃, 300 MHz): 1.38 (d, J=8, 3H), 2.18 (s, 3H), 2.30–2.40 (m, 12H), 2.47 93, 3H), 2.60–2.75 (m, 2H), 4.30–4.50 (m, 1H), 6.60–6.70 (m, 1H), 7.00–7.15 (m, 3H).

z) CI-HRMS: Calcd: 361.2140, Found: 361.2128 (M+H); NMR (CDCl₃, 300 MHz): 0.75–0.83 (m, 2H), 1.00–1.10 (m, 2H), 2.17 (s, 3H), 2.30 (s, 3H), 2.36 (s, 3H), 2.47 (s, 3H), 2.85 (t, J=8, 2H), 3.30–3.40 (m, 1H), 4.40–4.55 (m, 2H), 7.00–7.18 (m, 3H).

aa) CI-HRMS: Calcd: 363.2297, Found: 363.2311 (M+H); NMR (CDCl₃, 300 MHz): 1.01 (t, 3H, J=8), 1.75–1.90 (m,2H), 2.15 (s,3H), 2.19 (s, 3H), 2.35 (s, 3H), 2.40 (s, 3H), 2.40 (s, 3H), 2.98 (t, 2H, J=8), 3.97–4.15 (m, 2H), 4.15–4.30 (m, 2H), 7.03(d, 1H, 1H), 7.08 (d, 1H, J=8), 7.10 (s, 1H).

ab) CI-HRMS: Calcd: 363.2297, Found: 363.2295 (M+H); NMR (CDCl₃, 300 MHz): 1.01 (t, 3H, J=8), 1.35–1.55 (m, 2H), 1.75–1.90 (m, 2H), 2.15 (s, 3H), 2.30 (s, 3H), 2.36 (s, 3H), 2.46 (s, 3H), 4.10–4.30 (m, 2H), 4.95–5.10 (br s, 2H), 7.05 (d, 1H, J=8), 7.10 (d, 1H, J=8), 7.15 (s, 1H).

ac) CI-HRMS: Calcd: 368.2450, Found: 368.2436; Analysis: Calcd: C, 68.62, H, 7.95, N, 19.06; Found: C, 68.73, H, 7.97, N, 19.09; NMR (CDCl₃, 300 MHz): 1.05 (t, J=8, 3H), 1.70–1.90 (m, 2H), 2.01 (d, J=3, 6H), 2.20 (s, 3H), 2.30 (s, 3H), 2.46, 2.465 (s, s, 3H), 3.42, 3.48 (s, s, 3H), 3.53–3.63 (m, 2H), 4.35–4.45 (m, 1H), 6.73 (d, J=8, 1H), 6.97 (s, 2H).

(ad) CI-HRMS: Calcd: 352.2501, Found: 352.2500 (M+H): Analysis: Calcd: C, 71.76; H, 8.33; N: 19.92, Found: C, 71.55; H, 8.15; N, 19.28; NMR (CDCl₃, 300 MHz): 1.01(t, J=8, 6H), 1.58–1.70 (m, 2H), 1.70–1.85 (m, 2H), 2.02 (s, 6H), 2.19 (s, 3H), 2.45 (s, 3H), 4.12–4.28 (m, 1H), 6.18 (d, J=8, 1H), 6.95 (s, 2H).

(ae) CI-HRMS: Calcd: 398.2556, Found: 398.2551 (M+H); Analysis: Calcd: C, 66.47; H, 7.86; N, 17.62, Found: C, 66.74; H, 7.79; N, 17.70; NMR (CDCl₃, 300 MHz): 2.00 (s, 6H), 2.12 (s, 3H), 2.30 (s, 3H), 2.37 (s, 3H), 3.40 (s, 6H), 3.78 (t, J=8, 4H), 4.25–4.40 (m, 4H), 6.93 (s, 2H).

(af) CI-HRMS: Calcd: 450.1141, Found: 450.1133 (M+H); Analysis: Calcd: C, 50.67; H, 5.37; N, 15.55; Br: 17.74; Found: C, 52.36; H, 5.84; N, 14.90; Br: 17.44; NMR (CDCl₃, 300 MHz): 2.32 (s, 3H), 2.57 (s, 3H), 3.42 (s, 6H), 3.60 (q, J=8, 2H), 3.69 (q, J=8, 2H), 3.82 (s, 3H), 4.60–4.70 (m, 1H), 6.73 (d, J=8, 1H), 6.93 (dd, J=8, 1, 1H), 7.22 (d, J=8, 1H).

ag) CI-HRMS: Calcd: 434.1192, Found: 434.1169 (M+H); Analysis: Calcd: C, 52.54; H, 5.58; N, 16.12; Br: 18.40; Found: C, 52.57; H, 5.60; N, 15.98; Br: 18.22; NMR (CDCl₃, 300 MHz): 1.00–1.07 (m, 3H), 1.65–1.85 (m, 2H), 2.35 (s, 3H), 2.46, 2.47 (s, s, 3H), 3.40, 3.45 (s, s, 3H), 3.83 (s, 3H), 4.35–4.45 (m, 1H), 6.55 (d, J=8, 1H), 6.92 (dd, J=8, 1, 1H) 7.20–7.30 (m, 2H).

ah) CI-HRMS: Calcd: 337.2266, Found: 337.2251 (M+H); Analysis: Calcd: C, 70.18; H, 8.06; N, 20.75; Found: C, 70.69; H, 7.66; N: 20.34; NMR (CDCl₃, 300 MHz): 1.35 (t, J=8, 6H), 2.01 (s, 6H), 2.15 (s, 3H), 2.30 (s, 3H), 2.38 (s, 3H), 4.07 (q, J=8, 4H), 6.93 (s, 2H).

ai) CI-HRMS: Calcd: 412.2713, Found: 412.2687 (M+H); Analysis: Calcd: C, 67.13; H, 8.08; N, 17.02; Found: C, 67.22; H, 7.85; N, 17.13; NMR (CDCl₃, 300 MHz):1.24 (t, J=8, 6H), 2.00 (s, 6H), 2.20 (s, 3H), 2.30 (s, 3H), 2.43 (s, 3H), 3.60 (q, J=8, 4H), 3.66 (dd, J=8, 3, 2H), 3.75 (dd, J=8, 3, 2H), 4.55–4.65 (m, 1H), 6.75 (d, J=8, 1H), 6.95 (s, 2H).

aj) CI-HRMS: Calcd: 398.2556, Found: 398.2545 (M+H); Analysis: Calcd: C, 66.47; H, 7.86; N, 17.62; Found: C, 66.87; H, 7.62; N, 17.75; NMR (CDCl₃, 300 MHz): 1.95–2.10 (m, 8H), 2.20 (s, 3H), 2.32 (s, 3H), 2.44 (s, 3H), 3.38 (s, 3H), 3.42 (s, 3H), 3.50–3.70 (m, 4H), 4.58–4.70 (m, 1H), 6.87 (d, J=8, 1H), 6.95 (s, 2H).

ak) CI-HRMS: Calcd: 338.1981, Found: 338.1971 (M+H); Analysis: Calcd: C, 67.63; H, 6.87; N, 20.06; Found: C, 67.67; H, 6.82; N, 20.31; NMR (CDCl₃, 300 MHz): 2.15 (s, 3H), 2.29 (s, 3H), 2.35 (s, 3H), 2.43 (s, 3H), 3.90 (t, J=8, 4H), 4.35–4.45 (m, 4H), 7.00–7.15 (m, 3H).

al) CI-HRMS: Calcd: 464.1297, Found: 464.1297 (M+H); NMR (CDCl₃, 300 MHz): 2.28 (s, 3H), 2.40 (s, 3H), 3.40 (s, 6H), 3.75 (t, J=8, 4H), 3.83 (s, 3H), 4.20–4.50 (m, 4H), 6.93 (dd, J=8, 1, 1H), 7.20 (s, 1H), 7.24 (d, J=1, 1H).

am) CI-HRMS: Calcd: 418.1242, Found: 418.1223 (M+H); NMR (CDCl₃, 300 MHz): 1.00 (t, d, J=8, 1, 6H), 1.55–1.75 (m, 4H), 2.34 (s, 3H), 2.49 (s, 3H), 2.84 (s, 3H), 4.15–4.27 (m, 1H), 6.19 (d, J=8, 1H), 6.93 (dd, J=8, 1, 1H), 7.21–7.30 (m, 2H).

an) CI-HRMS: Calcd: 404.1086, Found: 404.1079(M+H); NMR (CDCl₃, 300 MHz): 1.35 (t, J=8, 6H), 2.28 (s, 3H), 2.40 (s, 3H), 3.83 (s, 3H), 3.90–4.08 (m, 2H), 4.08–4.20 (m, 2H), 6.92 (dd, J=8, 1, 1H), 7.20–7.25 (m, 2H).

ao) CI-HRMS: Calcd: 308.1875, Found: 308.1872 (M+H); NMR (CDCl₃, 300 MHz): 0.75–0.80 (m, 2H), 0.93–1.00 (m, 2H), 2.16 (s, 3H), 2.28 (s, 3H), 2.35 (s, 3H), 2.53 (s, 3H), 3.00–3.10 (m, 1H), 6.50–6.55 (m, 1H), 7.00–7.15 (m, 3H).

ap) CI-HRMS: Calcd: 397.1988, Found: 397.1984 (M+H); NMR (CDCl₃, 300 MHz): 2.43 (s, 3H), 2.50 (s, 3H), 3.43 (s, 3H), 3.61 (dd, J=8, 8, 2H), 3.69 (dd,J=8, 8, 2H), 3.88 (s, 3H), 4.58–4.70 (m, 1H), 6.75 (d, J=8, 1H), 7.20 (dd, J=8, 1, 1H), 7.25 (d, J=1, 1H), 7.40 (s, 1H).

aq) CI-HRMS: Calcd: 375.2297, Found: 375.2286 (M+H); Analysis: Calcd: C, 70.56; H, 7.01; N, 22.44; Found: C, 70.49; H, 6.99; N, 22.45; NMR (CDCl₃, 300 MHz): 0.79–0.85 (m, 2H), 1.00–1.05 (m, 1H), 2.00 (s, 6H), 2.19 (s, 3H), 2.32 (s, 3H), 2.44 (s, 3H), 2.84 (t, J=8, 2H), 3.30–3.40 (m, 1H), 4.50 (t, J=8, 2H), 6.95 (s, 2H).

ar) CI-HRMS: Calcd: 434.1192, Found: 434.1189 (M+H); Analysis: Calcd: C, 52.54; H, 5.58; N, 16.12; Br: 18.40; Found: C, 52.75; H, 5.59; N, 16.09; Br: 18.67; NMR (CDCl₃, 300 MHz): 2.19 (s, 3H), 2.30 (s, 3H), 2.47 (s, 3H), 3.43 (s, 6H), 3.60 (dd, J=8, 8, 2H), 3.70 (dd, J=8,8, 2H), 4.58–4.70 (m, 1H), 6.71 (d, J=8, 1H), 7.08 (d, J=8, 1H), 7.37 (dd, J=8, 1, 1H), 7.45 (d, J=1, 1H).

as) CI-HRMS: Calcd: 448.1348, Found: 448.1332 (M+H); Analysis: Calcd: C, 53.58; H, 5.85; N, 16.62; Br: 17.82; Found: C, 53.68; H, 5.74; N, 15.52; Br: 13.03; NMR (CDCl₃, 300 MHz): 1.95–2.10 (m, 2H), 2.20 (s, 3H), 2.30 (s, 3H), 2.47 (s, 3H), 3.38 (s, 3H), 3.41 (s, 3H), 3.50–3.67 (m, 4H), 4.55–4.70 (m, 1H), 6.89 (d, J=8, 1H), 7.05 (d, J=8, 1H), 7.35 (dd, J=8, 1, 1H), 7.47 (d, J=1, 1H).

at) CI-HRMS: Calcd: 400.2349, Found: 400.2348 (M+H); Analysis: Calcd: C: C, 63.14; H, 7.32; N, 17.53; Found: C, 63.40; H, 7.08; N, 17.14; NMR (CDCl₃, 300 MHz): 2.16 (s, 3H), 2.20 (s, 3H), 2.30 (s, 3H), 2.46 (s, 3H), 3.42 (s, 6H), 3.60 (q, J=8, 2H), 3.70 (q, J=8, 2H), 3.85 (s, 3H), 4.59–4.70 (m, 1H), 6.70 (d, J=8, 1H), 6.76 (s, 1H), 6.96 (s, 1H).

au) CI-HRMS: Calcd: 414.2505, Found: 414.2493 (M+H); NMR (CDCl₃, 300 MHz): 2.15 (s, 3H), 2.19 (s, 3H), 2.25 (s, 3H), 2.40 (s, 3H), 3.40 (s, 6H), 3.76 (t, J=8, 4H), 3.84 (s, 3H), 4.20–4.45 (m, 4H), 6.77 (s, 1H), 6.93 (s, 1H).

av) CI-HRMS: Calcd: 368.2450, Found: 368.2447 (M+H); NMR (CDCl₃, 300 MHz): 1.00 (t, J=8, 6H), 1.55–1.85 (m, 4H), 2.19 (s, 3H), 2.20 (s, 3H), 2.30 (s, 3H), 2.47 (s, 3H), 3.88 (s, 3H), 4.10–4.30 (m, 1H), 6.15 (d, J=8, 1H), 6.78 (s, 1H), 6.98 (s, 1H).

aw) CI-HRMS: Calcd: 353.2216, Found: 353.2197 (M+H); NMR (CDCl₃, 300 MHz): 1.35 (t, J=8, 6H), 2.17 (s, 3H), 2.19 (s, 3H), 2.28 (s, 3H), 2.40 (s, 3H), 3.85 (s, 3H), 3.90–4.20 (m, 4H), 6.78 (s, 1H), 6.95 (s, 1H).

ax) CI-HRMS: Calcd: 390.1697, Found: 390.1688 (M+H); Analysis: Calcd: C, 58.53; H, 6.20; N, 17.96; Cl: 9.09; Found: C, 58.95; H, 6.28; N, 17.73; Cl: 9.15; NMR (CDCl₃, 300 MHz): 2.35 (s, 3H), 2.37 (s, 3H), 2.48 (s, 3H), 3.42 (s, 6H), 3.60 (dd, J=8, 8, 2H) 3.68 (dd, J=8, 8, 2H), 4.59–4.72 (m, 1H), 6.72 (d, J=8, 1H), 7.12 (d, J=8, 1H), 7.23 (d, J=8, 1H), 7.32 (s, 1H).

ay) CI-HRMS: Calcd: 374.1748, Found: 374.1735 (M+H); Analysis: Calcd: C, 61.04; H, 6.47; N, 18.73; Cl: 9.48; Found: C, 61.47; H, 6.54; N, 18.23; Cl: 9.61; NMR (CDCl₃,300 MHz): 1.01 (t, J=8, 3H), 1.62–1.88 (m, 4H), 2.35 (s, 3H), 2.37 (s, 3H), 2.48 (d, J=1, 3H), 3.40, 3.45 (s, s, 3H), 3.50–3.64 (m, 2H), 4.38–4.47 (m, 1H), 6.53 (d, J=8, 1H), 7.12 (d, J=8, 1H), 7.07 (d, J=8, 1H), 7.12 (s, 1H).

az) CI-HRMS: Calcd: 404.1853, Found: 404.1839 (M+H); NMR (CDCl₃, 300 MHz): 2.29 (s, 3H), 2.38 (s, 3H), 2.40 (s, 3H), 3.40 (s, 6H), 3.76 (t, J=8, 4H), 4.20–4.45 (m, 4H), 7.11 (d, J=8, 1H), 7.22 (d, J=8, 1H), 7.31 (s, 1H).

ba) CI-HRMS: Calcd: 404.1853, Found: 404.1859 (M+H); Analysis: C, 59.47; H, 6.50; N, 17.34; Cl: 8.79; Found: C, 59.73; H, 6.46; N, 17.10; Cl: 8.73; NMR (CDCl₃, 300 MHz): 1.95–2.08 (m, 2H), 2.35 (s, 3H), 2.38 (s, 3H), 2.46 (s, 3H), 3.38 (s, 3H), 3.41 (s, 3H), 3.50–3.65 (m, 4H), 4.56–4.70 (m, 1H), 6.85 (d, J=8, 1H), 7.12 (d, J=8, 1H), 7.45 (d, J=8, 1H), 7.32 (s, 1H).

bb) CI-HRMS: Calcd: 391.2246, Found: 391.2258 (M+H); Analysis: C, 67.67; H, 6.71; N, 21.52; Found: C: 67.93; H, 6.70; N, 21.48; NMR (CDCl₃, 300 MHz): 0.76–0.84 (m, 2H), 0.84–0.91 (m, 2H), 1.00–1.08 (m, 2H), 2.15 (s, 3H), 2.20 (s, 3H), 2.29 (s, 3H), 2.45 (s, 3H), 2.85 (t, J=8, 2H), 3.28–3.30 (m, 1H), 3.85 (s, 3H), 6.78 (s, 1H), 6.95 (s, 1H).

bc) CI-HRMS: Calcd: 386.2192, Found: 386.2181 (M+H); Analysis: C, 62.32; H, 7.06; N, 18.17; Found: C: 62.48; H, 6.83; N, 18.15; NMR (CDCl₃, 300 MHz): 7.1 (d, 1H, J=8), 6.9 (d, 1H, J=1), 6.8 (dd, 1H, J=8,1), 6.7 (br. d, 1H, J=8), 4.7–4.6 (m, 1H), 3.85 (s, 3H), 3.70–3.55 (m, 4H), 3.45 (s, 6H), 2.5 (s, 3H), 2.3 (s, 3H), 2.15 (s, 3H).

bd) CI-HRMS: Calcd: 400.2349, Found: 400.2336 (M+H); NMR (CDCl₃, 300 MHz): 7.1 (d, 1H, J=7), 6.85 (d, 1H, J=1), 6.75 (dd, 1H, J=7,1), 4.45–4.25 (br.s, 4H), 3.75 (t, 4H, J=7), 3.4 (s, 6H), 2.4 (s, 3H), 2.25 (s, 3H), 2.15 (s, 3H).

be) CI-HRMS: Calcd: 370.2243, Found: 370.2247 (M+H); Analysis: C, 65.02; H, 7.38; N, 18.96; Found: C: 65.28; H, 7.27; N, 18.71; NMR (CDCl₃, 300 MHz): 7.1 (d, 1H, J=8), 6.85 (d, 1H, J=1), 6.8 (dd, 1H, J=8,1), 6.5 (br. d, 1H, J=1), 4.5–4.3 (m, 1H), 3.85 (s, 3H), 3.65–3.5 (m, 2H), 3.4 (s, 2H), 2.5 (s, 3H), 2.3 (s, 3H), 2.2 (s, 3H), 1.9–1.7 (m, 2H), 1.05 (t, 3H, J=7).

bf) CI-HRMS: Calcd: 379.2246, Found: 379.2248 (M+H); NMR (CDCl₃, 300 MHz): 7.1 (d, 1H, J=8), 6.85 (d, 1H, J=1), 6.8 (dd, 1H, J=8,1), 4.3–4.0 (m, 4H), 3.85 (s, 3H), 3.0 (t, 2H, J=7), 2.45 (s, 3H), 2.3 (s, 3H), 2.2 (s, 3H), 1.9–1.8 (m, 2H) 1.0 (t, 3H, J=7).

bg) CI-HRMS: Calcd: 340.2137, Found: 340.2122 (M+H); NMR (CDCl₃, 300 MHz): 7.1 (d, 1H, J=8), 6.85 (d, 1H, J=1), 6.75 (dd, 1H, J=8,1), 4.2–4.0 (br.m, 4H), 3.85 (s, 3H, 2.4 (s, 3H), 2.3 (s, 3H), 2.2 (s, 3H), 1.35 (t, 6H, J=7).

bh) CI-HRMS: Calcd: 313.1665, Found: 313.6664 (M+H).

bi) CI-HRMS: Calcd: 400.2349, Found: 400.2346 (M+H); NMR (CDCl₃, 300 MHz): 7.1 (d, 1H, J=7), 6.9–6.75 (m, 3H), 4.7–4.55 (m, 1H), 3.8 (s, 3H), 3,7–3.5 (m, 4H), 3.45 (s, 3H), 3.35 (s, 3H), 2.5 (s, 3H), 2.3 (s, 3H), 2.2 (s, 3H), 2.1–1.95 (m, 2H).

bj) CI-HRMS: Calcd: 377.2090, Found: 377.2092 (M+H); Analysis: C, 67.00; H, 6.44; N, 22.32; Found: C: 67.35; H, 6.44; N, 22.23; NMR (CDCl₃, 300 MHz): 7.1 (d, 1H, J=8), 6.9 (d, 1H, J=1), 6.8 (dd, 1H, J=8,1), 4.55–4.4 (m, 2H), 3.85 (s, 3H), 3.4–3.3 (m, 1H), 2.85 (t, 2H, J=7), 2.5 (s, 3H), 2.3 (s, 3H), 2.2 (s, 3H), 1.11.0 (m, 2H), 0.85–0.75 (m, 2H).

bk) CI-HRMS: Calcd: 413.2427, Found: 413.2416 (M+H); NMR (CDCl₃, 300 Hz): 7.1 (d, 1H, J=8), 6.85 (d, 1H, J=1), 6.75 (dd, 1H, J=8,1), 4.6 (m, 1H), 3.85 (s, 3H), 3.75–3.6(m, 4H), 3.6 (q, 4H, J=7), 2.5 (s, 3H), 2.3 s, 3H), 2.2 (s, 3H), 1.25 (t, 6H, J=7).

bl) CI-HRMS: Calcd: 420.1802, Found: 420.1825(M+H);

bm) CI-HRMS: Calcd: 390.1697, Found: 390.1707(M+H);

bn) CI-HRMS: Calcd: 397.1465, Found: 397.1462(M+H);

bo) CI-HRMS: Calcd: 360.1513, Found: 360.1514(M+H);

bp) CI-HRMS: Calcd: 374.1748, Found: 374.1737(M+H);

bq) CI-HRMS: Calcd: 479.1155, Found: 479.1154(M+H);

br) CI-HRMS: Calcd: 463.1219, Found: 463.1211(M+H); Analysis Calcd: C, 51.96, H, 5.23, N, 15.15, Br: 17.28; Found: C, 52.29, H, 5.62, N, 14.79, Br: 17.47

bs) CI-HRMS: Calcd: 433.1113, Found: 433.1114(M, ⁷⁹Br);

bt) NH₃—CI MS: Calcd: 406, Found: 406 (M+H)+; NMR (CDCl₃, 300 MHz):δ7.28 (d, J=10 Hz, 1H), 7.03 (d, J=8 Hz, 1H), 6.96 (s, 1H), 6.7 (d, J=9, 1H), 4.63 (m, 1H), 3.79 (s, 3H), 3.6 (m, 4H), 3.42 (s, 6H), 2.47 (s, 3H), 2.32 (s, 3H).

Example 431 Preparation of 2,4,7-dimethyl-8-(4-methoxy-2-methylphenyl)[1,5-a]-pyrazolo-1,3,5-triazine (Formula 1, where R³ is CH₃, R₁ is CH₃, Z is C—CH₃, Ar is 2,4-dimethylphenyl)

5-Acetamidino-4-(4-methoxy-2-methylphenyl)-3-methylpyrazole, acetic acid salt (602 mg, 2 mmol) was mixed with a saturated NaHCO₃ solution (10 mL). The aqueous mixture was extracted with EtOAc three times. The combined organic layers were dried over MgSO₄, filtered and concentrated in vacuo. The residue was taken up in toluene (10 mL) and trimethyl orthoacetate (0.36 g, 3 mmol) was added to the suspension. The reaction mixture was heated to reflux temperature under a nitrogen atmosphere and stirred for 16 hours. After being cooled to ambient temperature, the reaction mixture was concentrated in vacuo to give an oily solid. Column chromatography (CHCl₃:MeOH::9:1) afforded, after removal of solvent in vacuo, a yellow viscous oil (Rf=0.6, 210 mg, 37% yield): NMR (CDCl₃, 300 MHz): 7.15 (d, 1H, J=8), 6.9 (d, 1H, J=1), 6.85 (dd, 1H, J=8,1), 3.85 (s, 3H), 2.95 (s, 3H), 2.65 (s, 3H), 2.4 (s, 3H), 2.15 (s, 3H); CI-HRMS: Calcd: 283.1559, Found: 283.1554 (M+H).

Example 432 7-hydroxy-5-methyl-3-(2-chloro-4-methylphenyl)pyrazolo[1,5-a]pyrimidine (Formula 1 where A is CH, R1 is Me, R³ is OH, Z is C-Me, Ar is 2-chloro-4-methylphenyl)

5-Amino-4-(2-chloro-4-methylphenyl)-3-methylpyrazole (1.86 g, 8.4 mmol) was dissolved in glacial acetic acid (30 mL) with stirring. Ethyl acetoacetate (1.18 mL, 9.2 mmol) was then added dropwise to the resulting solution. The reaction mixture was then heated to reflux temperature and stirred for 16 hours, then cooled to room temperature. Ether (100 mL) was added and the resulting precipitate was collected by filtration. Drying in vacuo afforded a white solid (1.0 g, 42% yield): NMR (CDCl₃, 300 Hz): 8.70 (br.s 1H), 7.29 (s, 1H), 7.21–7.09 (m, 2H), 5.62 (s, 1H), 2.35 (s, 6H), 2.29 (s, 3H); CI-MS: 288 (M+H).

Example 433 7-chloro-5-methyl-3-(2-chloro-4-methylphenyl)pyrazolo[1,5-a]pyrimidine (Formula 1 where A is CH, R1 is Me, R³ is Cl, Z is C-Me, Ar is 2-chloro-4-methylphenyl)

A mixture of 7-hydroxy-5-methyl-3-(2-chloro-4-methylphenyl)-pyrazolo[1,5-a]pyrimidine (1.0 g, 3.5 mmol), phosphorus oxychloride (2.7 g, 1.64 mL, 17.4 mmol), N,N-diethylaniline (0.63 g, 0.7 mL, 4.2 mmol) and toluene (20 mL) was stirred at reflux temperature for 3 hours, then it was cooled to ambient temperature. The volatiles were removed in vacuo. Flash chromatography (EtOAc:hexane::1:2) on the residue gave 7-chloro-5-methyl-3-(2-chloro-4-methylphenyl)pyrazolo[1,5-a]pyrimidine (900 mg, 84% yield) as a yellow oil: NMR (CDCl₃, 300 Hz): 7.35 (s, 1H), 7.28–7.26 (m, 1H), 71.6 (d, 1H, J=7), 6.80 (s, 1H), 2.55 (s, 3H), 2.45 (s, 3H), 2.40 (s, 3H); CI-MS: 306 (M+H).

Example 434 7-(pentyl-3-amino)-5-methyl-3-(2-chloro-4-methylphenyl)pyrazolo[1,5-a]pyrimidine (Formula 1 where A is CH, R1 is Me, R3 is pentyl-3-amino, Z is C-Me, Ar is 2-chloro-4-methylphenyl)

A solution of substituents independently selected at

-   -   each occurrence from C₁–C₆ alkyl, C₃–C₆ cycloalkyl, halo, C₁–C₄         haloalkyl, cyano, OR¹⁵, SH, S(O)_(n)R¹³, COR¹⁵, CO₂R¹⁵,         OC(O)R¹³, NR⁸COR¹⁵, N(COR¹⁵)₂, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵,         CONR¹⁶R¹⁵, aryl, heteroaryl or heterocyclyl,     -   -aryl, aryl(C₁–C₄ alkyl), heteroaryl, heteroaryl(C₁–C₄ alkyl),         heterocyclyl or heterocyclyl(C₁–C₄ alkyl);         3-pentylamine (394 mg, 6.5 mmol) and         7-chloro-5-methyl-3-(2-chloro-4-methylphenyl)pyrazolo[1,5-a]pyrimidine         (200 mg, 0.65 mmol) in dimethylsulfoxide (DMSO, 10 mL) was         stirred at 150° C. for 2 hours; then it was cooled to ambient         temperature. The reaction mixture was then poured onto water         (100 mL) and mixed. Three extractions with dichloromethane,         washing the combined organic layers with brine, drying over         MgSO₄, filtration and removal of solvent in vacuo produced a         yellow solid. Flash chromatography (EtOAc:hexanes::1:4) afforded         a white solid (140 mg, 60% yield): mp 139–141° C.; NMR (CDCl₃,         300 Hz):7.32 (s, 1H), 7.27 (d, 1H, J=8), 7.12 (d, 1H, J=7), 6.02         (d, 1H, J=9), 5.78 (s, 1H), 3.50–3.39 (m, 1H), 2.45 (s, 3H),         2.36 (s, 6H), 1.82–1.60 (m, 4H), 1.01 (t, 6H, J=8); Analysis         Calcd for CO₂OH₂₅ClN₄: C, 67.31, H, 7.06, N, 15.70, Cl: 9.93;         Found: C, 67.32, H, 6.95, N, 15.50, Cl, 9.93.

The examples delineated in TABLE 2 may be prepared by the methods outlined in Examples 1A, 1B, 432, 433, 434. Commonly used abbreviations are: Ph is phenyl, Pr is propyl, Me is methyl, Et is ethyl, Bu is butyl, Ex is Example, EtOAc is ethyl acetate.

TABLE 2

Ex. Z R₃ Ar mp(° C.) 435^(b) C—Me N(CH₂CH₂OMe)₂ 2,4-Cl₂—Ph 71–73 436^(c) C—Me N(Bu)Et 2,4-Cl₂—Ph 86–87 437^(d) C—Me NHCH(Et)CH₂OMe 2,4-Cl₂—Ph 110–111 438^(e) C—Me N(Pr)CH₂CH₂CN 2,4-Cl₂—Ph 83–85 439^(f) C—Me NH-3-pentyl 2,4-Cl₂—Ph 175–176 440^(g) C—Me NHCH(CH₂OMe)₂ 2,4-Cl₂—Ph 107 441^(h) C—Me NHCH(Et)₂ 2,4-Me₂—Ph oil 442^(i) C—Me NHCH(CH₂OMe)₂ 2,4-Me₂—Ph 103–105 443^(j) C—Me N(CH₂CH₂OMe)₂ 2,4-Me₂—Ph 87–89 444^(k) C—Me N(c-Pr)CH₂CH₂CN 2,4-Me₂—Ph 133 (dec) 445^(l) C—Me N(CH₂CH₂OMe)₂ 2-Cl,4-MePh 77–78 446^(m) C—Me NHCH(CH₂OMe)₂ 2-Cl,4-MePh 131–133 447^(n) C—Me NHCH(Et)₂ 2-Cl,4-MePh 139–141 448^(o) C—Me NEt₂ 2,4-Me₂—Ph 92–94 449^(p) C—Me N(Pr)CH₂CH₂CN 2,4-Me₂—Ph 143–144 450^(q) C—Me N(Bu)CH₂CH₂CN 2,4-Me₂—Ph 115–117 451^(r) C—Me NHCH(Et)CH₂OMe 2,4-Me₂—Ph oil 452^(s) C—Me NHCH(Et)₂ 2-Me,4-MeOPh 104–106 453^(t) C—Me NHCH(CH₂OMe)₂ 2-Me,4-MeOPh 115–116 454^(u) C—Me N(CH₂CH₂OMe)₂ 2-Me,4-MeOPh oil 455^(v) C—Me (S)-NHCH(CH₂CH₂OMe)—(CH₂OMe) 2-Me,4-MeOPh oil 456^(w) C—Me (S)-NHCH(CH₂CH₂OMe)—(CH₂OMe) 2,4-Me₂—Ph oil 457^(x) C—Me N(CH₂CH₂OMe)₂ 2-Me,4-ClPh oil 458^(y) C—Me NHEt 2,4-Me₂—Ph oil 459^(z) C—Me NHCH(Et)₂ 2-Me,4-ClPh 94–96 460^(aa) C—Me NHCH(CH₂OMe)₂ 2-Me,4-ClPh 113–114 461^(ab) C—Me N(Ac)Et 2,4-Me₂—Ph oil 462^(ac) C—Me (S)-NHCH(CH₂CH₂OMe)—(CH₂OMe) 2-Me,4-ClPh oil 463^(ad) C—Me N(Pr)CH₂CH₂CN 2-Me,4-MeOPh 118–119 464^(ae) C—Me NEt₂ 2-Me,4-MeOPh 97–99 465^(af) C—Me (S)-NHCH(CH₂CH₂OMe)—(CH₂OMe) 2-Cl,4-MePh 101–103 466^(ag) C—Me NEt₂ 2-Cl,4-MePh 129–130 467^(ah) C—Me N(c-Pr)CH₂CH₂CN 2-Me,4-MeOPh 177–178 468^(ai) C—Me N(c-Pr)CH₂CH₂CN 2-Cl,4-MePh 162–163 469^(aj) C—Me NHCH(Et)CH₂OMe 2-Me,4-MeOPh oil 470^(ak) C—Me NHCH(Et)CH₂OMe 2-Cl,4-MePh 111–113 471 C—Me NHCH(CH₂OMe)₂ 2-Cl-4-MeOPh 472 C—Me N(CH₂CH₂OMe)₂ 2-Cl-4-MeOPh 473 C—Me NHCH(Et)CH₂OMe 2-Cl-4-MeOPh 474 C—Me N(c-Pr)CH₂CH₂CN 2-Cl-4-MeOPh 475 C—Me NEt₂ 2-Cl-4-MeOPh 476 C—Me NH-3-pentyl 2-Cl-4-MeOPh 477 C—Me NHCH(Et)CH₂CH₂OMe 2-Cl-4-MeOPh 478 C—Me NHCH(Me)CH₂CH₂OMe 2-Cl-4-MeOPh 479 C—Me NHCH(Et)CH₂CH₂OMe 2-Br-4-MeOPh 480 C—Me NHCH(Me)CH₂CH₂OMe 2-Br-4-MeOPh 481 C—Me NHCH(Et)CH₂CH₂OMe 2-Me-4-MeOPh 482 C—Me NHCH(Me)CH₂CH₂OMe 2-Me-4-MeOPh 483 C—Me NHCH(CH₂OMe)₂ 2-Cl-4,5-(MeO)₂Ph 484 C—Me N(CH₂CH₂OMe)₂ 2-Cl-4,5-(MeO)₂Ph 485 C—Me NHCH(Et)CH₂OMe 2-Cl-4,5-(MeO)₂Ph 486 C—Me N(c-Pr)CH₂CH₂CN 2-Cl-4,5-(MeO)₂Ph 487 C—Me NEt₂ 2-Cl-4,5-(MeO)₂Ph  99–101 488 C—Me NH-3-pentyl 2-Cl-4,5-(MeO)₂Ph 169–170 489 C—Me NHCH(Et)CH₂CH₂OMe 2-Cl-4,5-(MeO)₂Ph 490 C—Me NHCH(Me)CH₂CH₂OMe 2-Cl-4,5-(MeO)₂Ph 491 C—Me NHCH(CH₂OMe)₂ 2-Br-4,5-(MeO)₂Ph 90–93 492 C—Me N(CH₂CH₂OMe)₂ 2-Br-4,5-(MeO)₂Ph 110 493 C—Me NHCH(Et)CH₂OMe 2-Br-4,5-(MeO)₂Ph 494 C—Me N(c-Pr)CH₂CH₂CN 2-Br-4,5-(MeO)₂Ph 495 C—Me NEt₂ 2-Br-4,5-(MeO)₂Ph 496 C—Me NH-3-pentyl 2-Br-4,5-(MeO)₂Ph 497 C—Me NHCH(Et)CH₂CH₂OMe 2-Br-4,5-(MeO)₂Ph 498 C—Me NHCH(Me)CH₂CH₂OMe 2-Br-4,5-(MeO)₂Ph 499 C—Me NHCH(CH₂OMe)₂ 2-Cl-4,6-(MeO)₂Ph 500 C—Me N(CH₂CH₂OMe)₂ 2-Cl-4,6-(MeO)₂Ph 501 C—Me NHCH(Et)CH₂OMe 2-Cl-4,6-(MeO)₂Ph 502 C—Me N(c-Pr)CH₂CH₂CN 2-Cl-4,6-(MeO)₂Ph 503 C—Me NEt₂ 2-Cl-4,6-(MeO)₂Ph 504 C—Me NH-3-pentyl 2-Cl-4,6-(MeO)₂Ph 505 C—Me NHCH(Et)CH₂CH₂OMe 2-Cl-4,6-(MeO)₂Ph 506 C—Me NHCH(Me)CH₂CH₂OMe 2-Cl-4,6-(MeO)₂Ph 507 C—Me NHCH(CH₂OMe)₂ 2-Me-4,6-(MeO)₂Ph 508 C—Me N(CH₂CH₂OMe)₂ 2-Me-4,6-(MeO)₂Ph 509 C—Me NHCH(Et)CH₂OMe 2-Me-4,6-(MeO)₂Ph 510 C—Me N(c-Pr)CH₂CH₂CN 2-Me-4,6-(MeO)₂Ph 511 C—Me NEt₂ 2-Me-4,6-(MeO)₂Ph 512 C—Me NH-3-pentyl 2-Me-4,6-(MeO)₂Ph 513 C—Me NHCH(Et)CH₂CH₂OMe 2-Me-4,6-(MeO)₂Ph 514 C—Me NHCH(Me)CH₂CH₂OMe 2-Me-4,6-(MeO)₂Ph 515 C—Me N(c-Pr)CH₂CH₂CN 2-Br-4,6-(MeO)₂Ph 516 C—Me NEt₂ 2-Br-4,6-(MeO)₂Ph 517 C—Me NH-3-pentyl 2-Br-4,6-(MeO)₂Ph 518 C—Me NHCH(Et)CH₂CH₂OMe 2-Br-4,6-(MeO)₂Ph 519 C—Me NHCH(Me)CH₂CH₂OMe 2-Br-4,6-(MeO)₂Ph 520 C—Me NHCH(Et)CH₂CH₂OMe 2-Me-4-MeOPh 521 C—Me NHCH(Me)CH₂CH₂OMe 2-Me-4-MeOPh 522 C—Me NHCH(CH₂OMe)₂ 2-MeO-4-MePh 523 C—Me N(CH₂CH₂OMe)₂ 2-MeO-4-MePh 524 C—Me NHCH(Et)CH₂OMe 2-MeO-4-MePh 525 C—Me N(c-Pr)CH₂CH₂CN 2-MeO-4-MePh 526 C—Me NEt₂ 2-MeO-4-MePh 527 C—Me NH-3-pentyl 2-MeO-4-MePh 528 C—Me NHCH(Et)CH₂CH₂OMe 2-MeO-4-MePh 529 C—Me NHCH(Me)CH₂CH₂OMe 2-MeO-4-MePh 530 C—Me NHCH(CH₂OMe)₂ 2-MeO-4-MePh 531 C—Me N(CH₂CH₂OMe)₂ 2-MeO-4-MePh 532 C—Me NHCH(Et)CH₂OMe 2-MeO-4-MePh 533 C—Me N(c-Pr)CH₂CH₂CN 2-MeO-4-MePh 534 C—Me NEt₂ 2-MeO-4-MePh 535 C—Me NH-3-pentyl 2-MeO-4-MePh 536 C—Me NHCH(Et)CH₂CH₂OMe 2-MeO-4-MePh 537 C—Me NHCH(Me)CH₂CH₂OMe 2-MeO-4-MePh 538 C—Me NHCH(CH₂OMe)₂ 2-MeO-4-ClPh 539 C—Me N(CH₂CH₂OMe)₂ 2-MeO-4-ClPh 540 C—Me NHCH(Et)CH₂OMe 2-MeO-4-ClPh 541 C—Me N(c-Pr)CH₂CH₂CN 2-MeO-4-ClPh 542 C—Me NEt₂ 2-MeO-4-ClPh 543 C—Me NH-3-pentyl 2-MeO-4-ClPh 544 C—Me NHCH(Et)CH₂CH₂OMe 2-MeO-4-ClPh 545 C—Me NHCH(Me)CH₂CH₂OMe 2-MeO-4-ClPh

Notes for Table 2:

b) CI-HRMS: Calcd: 423.1355; Found: 423.1337 (M+H).

c) Analysis: Calcd: C, 61.38, H, 6.18, N, 14.32: Found: C, 61.54, H, 6.12, N, 14.37.

d) Analysis: Calcd: C, 58.02, H, 5.65, N, 14.24; Found: C, 58.11, H, 5.52, N, 14.26.

e) Analysis: Calcd: C, 59.71, H, 5.26, N, 14.85; Found: C, 59.94, H, 5.09, N, 17.23.

f) Analysis: Calcd: C, 60.48, H, 5.89, N, 14.85, Found: C, 60.62, H, 5.88, N, 14.82.

h) CI-HRMS: Calcd: 337.2388; Found: 337.2392 (M+H).

i) Analysis: Calcd: C, 68.45, H, 7.669, N, 15.21, Found: C, 68.35, H, 7.49 N, 14.91.

j) Analysis: Calcd: C, 69.08, H, 7.915, N, 14.65, Found: C, 68.85, H, 7.83, N, 14.54.

k) Analysis: Calcd: C, 73.51, H, 7.01, N, 19.48, Found: C, 71.57, H, 7.15, N, 19.12.

l) CI-HRMS: Calcd: 403.1899; Found: 403.1901 (M+H).

m) Analysis: Calcd: C, 61.77, H, 6.49, N, 14.41, Cl. 9.13; Found: C, 61.90, H, 6.66, N, 13.62, Cl, 9.25.

n) Analysis: Calcd: C, 67.31, H, 7.06, N, 15.70, Cl. 9.93; Found: C, 67.32, H, 6.95, N, 15.50, Cl, 9.93.

o) Analysis: Calcd:. C, 74.50, H, 8.14, N, 17.38, Found: C, 74.43, H, 7.59, N, 17.16.

p) Analysis: Calcd: C, 73.10, H, 7.54, N, 19.37, Found: C, 73.18, H, 7.59, N, 18.81.

q) Analysis: Calcd: C, 73.57, H, 7.78, N, 18.65, Found: C, 73.55, H, 7.79, N, 18.64.

r) CI-HRMS: Calcd: 353.2333; Found: 353.2341 (M+H).

s) Analysis: Calcd: C, 71.56, H, 8.02, N, 15.90, Found: C, 71.45, H, 7.99, N, 15.88.

t) Analysis: Calcd: C, 65.60, H, 7.34, N, 14.57, Found: C, 65.42, H, 7.24, N, 14.37.

u) CI-HRMS: Calcd: 399.2398; Found: 399.2396 (M+H).

v) CI-HRMS: Calcd: 399.2398; Found: 399.2396 (M+H).

w) CI-HRMS: Calcd: 383.2450; Found: 383.2447 (M+H).

x) CI-HRMS: Calcd: 403.1887; Found: 403.1901 (M+H).

y) CI-HRMS: Calcd: 295.1919; Found: 295.1923 (M+H).

z) Analysis: Calcd: C, 67.31, H, 7.06, N, 15.70, Found: C, 67.12, H, 6.86, N, 15.53.

aa) Analysis: Calcd: C, 61.77, H, 6.49, N, 14.41, Cl, 9.13; Found: C, 62.06, H, 6.37, N, 14.25, Cl, 9.12.

ab) CI-HRMS: Calcd: 337.2017; Found: 337.2028 (M+H).

ac) CI-HRMS: Calcd: 403.1893; Found: 403.1901 (M+H).

ad) Analysis: Calcd: C, 70.00, H, 7.22, N, 18.55, Found: C, 70.05, H, 7.22, N, 18.36.

ae) Analysis: Calcd: C, 70.98, H, 7.74, N, 16.55, Found: C, 71.15, H, 7.46, N, 16.56.

ag) Analysis: Calcd: C, 66.59, H, 6.76, N, 16.34, Found: C, 66.69, H, 6.82, N, 16.20.

ah) Analysis: Calcd: C, 70.38, H, 6.71, N, 18.65, Found: C, 70.35, H, 6.82, N, 18.83.

ai) Analysis: Calcd: C, 66.39, H, 5.85, N, 18.44, Cl, 9.33; Found: C, 66.29, H, 5.51, N, 18.36, Cl, 9.31.

aj) CI-HRMS: Calcd: 369.2278; Found: 369.2291 (M+H).

ak) Analysis: Calcd: C, 64.42, H, 6.77, N, 15.02, Found: C, 64.59, H, 6.51, N, 14.81.

The examples delineated in TABLE 3 may be prepared by the methods outlined in Examples 1, 2, 3 or 6. Commonly used abbreviations are: Ph is phenyl, Pr is propyl, Me is methyl, Et is ethyl, Bu is butyl, Ex is Example.

TABLE 3

Ex. Z R₃ Ar mp(° C.) 546^(a) C—Me NHCH(Et)₂ 2-Me-4-Me₂N—Ph 164–166 547^(b) C—Me S—NHCH(CH₂CH₂OMe)—CH₂OMe 2,4-Me2-Ph oil 548^(c) C—Me S—NHCH(CH₂CH₂OMe)—CH₂OMe 2-Me-4-Cl—Ph oil 549^(d) C—Me N(c-Pr)CH₂CH₂CN 2-Me-4-Cl—Ph 115–116 550^(e) C—Me NHCH(Et)CH₂CN 2-Me-4-Cl—Ph 131–132 551^(f) C—Me N(Et)₂ 2,3-Me₂-4-OMe—Ph oil 552^(g) C—Me N(CH₂CH₂OMe)CH₂CH₂OH 2,4-Cl₂—Ph oil 553^(h) C—Me N(CH₂CH₂OMe)₂ 2,3-Me₂-4-OMe—Ph oil 554^(i) C—Me NHCH(Et)₂ 2,3-Me₂-4-OMePh 123–124 555^(j) C—Me N(CH₂—c-Pr)Pr 2-Me-4-Cl—Ph oil 556^(k) C—Me N(c-Pr)CH₂CH₂CN 2,3-Me₂-4-OMePh 158–160 557 C—Me N(c-Pr)Et 2-Cl-4-OMePh 558 C—Me N(c-Pr)Me 2-Cl-4-OMePh 559 C—Me N(c-Pr)Pr 2-Cl-4-OMePh 560 C—Me N(c-Pr)Bu 2-Cl-4-OMePh 561^(l) C—Me N(Et)₂ 2-Cl-4-CN—Ph 115–117 562 C—Me N(c-Pr)₂ 2-Cl-4-OMe 127–129 563^(m) C—Me NHCH(CH₂OH)₂ 2,4-Cl₂—Ph 128–129 564 C—Me N(c-Pr)Et 2-Br-4,5-(MeO)2Ph 565 C—Me N(c-Pr)Me 2-Br-4,5-(MeO)2Ph 566 C—Me NH-c-Pr 2-Me-4-MeOPh 126–128 567 C—Me NHCH(Et)CH2OH 2-Me-4-MeOPh 60–62 568 C—Me NMe₂ 2-Br-4,5-(MeO)2Ph 569 C—Me NHCH(Et)₂ 2-Me-4-MeOPh 103–105 570 C—Me N(c-Pr)Et 2-Me-4-MeOPh 173–174 571 C—Me NH-2-pentyl 2,4-Cl₂—Ph 118–120 572 C—Me NHCH(Et)CH2CN 2,4-Cl₂—Ph 141–142 573 C—Me NHCH(Pr)CH2OMe 2,4-Cl₂—Ph 87–88 574 C—Me NHCH(CH2-iPr)CH2OMe 2,4-Cl₂—Ph amorphous 575 C—Me NH-2-butyl 2,4-Me₂—Ph oil 576 C—Me NH-2-pentyl 2,4-Me₂—Ph oil 577 C—Me NH-2-hexyl 2,4-Me₂—Ph oil 578 C—Me NHCH(i-Pr)Me 2,4-Me₂—Ph oil 579 C—Me NHCH(Me)CH2-iPr 2,4-Me₂—Ph oil 580 C—Me NHCH(Me)-c-C6H11 2,4-Me₂—Ph oil 581 C—Me NH-2-indanyl 2,4-Me₂—Ph oil 582 C—Me NH-1-indanyl 2,4-Me₂—Ph oil 583 C—Me NHCH(Me)Ph 2,4-Me₂—Ph oil 584 C—Me NHCH(Me)CH₂—(4-ClPh) 2,4-Me₂—Ph oil 585 C—Me NHCH(Me)CH₂COCH₃ 2,4-Me₂—Ph oil 586 C—Me NHCH(Ph)CH₂Ph 2,4-Me₂—Ph oil 587 C—Me NHCH(Me)(CH₂)3NEt₂ 2,4-Me₂—Ph oil 588 C—Me NH—(2-Ph-c-C₃H₄) 2,4-Me₂—Ph oil 589 C—Me NHCH(Et)CH₂CN 2,4-Me₂—Ph 119–120 590 C—Me NH-3-hexyl 2,4-Me₂—Ph oil 591^(n) C—Me NEt₂ 2-MeO-4-ClPh oil 592^(o) C—Me NHCH(Et)₂ 2-MeO-4-ClPh oil 593^(p) C—Me NHCH(Et)CH₂OMe 2-MeO-4-ClPh oil 594 C—Me NMe₂ 2-MeO-4-ClPh oil 595^(q) C—Me NHCH(Et)₂ 2-OMe-4-MePh oil 596^(r) C—Me NEt₂ 2-OMe-4-MePh oil 597^(s) C-c-Pr NHCH(CH₂OMe)₂ 2,4-Cl₂—Ph oil 598 C—Me N(c-Pr)Et 2,4-Me₂—Ph 599 C—Me N(c-Pr)Et 2,4-Cl₂—Ph 600 C—Me N(c-Pr)Et 2,4,6-Me₃—Ph 601 C—Me N(c-Pr)Et 2-Me-4-Cl—Ph 602 C—Me N(c-Pr)Et 2-Cl-4-Me—Ph 603 C—Me NHCH(c-Pr)₂ 2,4-Cl₂—Ph 604 C—Me NHCH(c-Pr)₂ 2,4-Me₂—Ph 605 C—Me NHCH(c-Pr)₂ 2-Me-4-Cl—Ph 606 C—Me NHCH(c-Pr)₂ 2-Cl-4-Me—Ph 607 C—Me NHCH(c-Pr)₂ 2-Me-4-OMe—Ph 608 C—Me NHCH(c-Pr)₂ 2-Cl-4-OMe—Ph 609 C—Me NHCH(CH₂OMe)₂ 2-Cl-5-F—OMePh 610 C—Me NEt₂ 2-Cl-5-F—OMePh 611 C—Me N(c-Pr)CH₂CH₂CN 2-Cl-5-F—OMePh 612 C—Me NHCH(Et)₂ 2-Cl-5-F—OMePh 613 C—Me N(CH₂CH₂OMe)₂ 2-Cl-5-F—OMePh 614 C—Me NEt₂ 2,6-Me₂-pyrid-3-yl 615 C—Me N(c-Pr)CH₂CH₂CN 2,6-Me₂-pyrid-3-yl 616 C—Me NHCH(Et)₂ 2,6-Me₂-pyrid-3-yl 617 C—Me N(CH₂CH₂OMe)₂ 2,6-Me₂-pyrid-3-yl 618 C—OH NHCH(CH₂OMe)₂ 2,4-Me₂—Ph 619 C—OH NEt₂ 2,4-Me₂—Ph 620 C—OH N(c-Pr)CH₂CH₂CN 2,4-Me₂—Ph 621 C—OH NHCH(Et)₂ 2,4-Me₂—Ph 623 C—OH N(CH₂CH₂OMe)₂ 2,4-Me₂—Ph 624 C—NEt₂ NHCH(CH₂OMe)₂ 2,4-Me₂—Ph 625 C—NEt₂ NEt₂ 2,4-Me₂—Ph 626 C—NEt₂ N(c-Pr)CH₂CH₂CN 2,4-Me₂—Ph 627 C—NEt₂ NHCH(Et)₂ 2,4-Me₂—Ph 628 C—NEt₂ N(CH₂CH₂OMe)₂ 2,4-Me₂—Ph 629 C—Me NHCH(Et)₂ 2-Me-4-CN—Ph 630 C—Me N(CH₂CH₂OMe)₂ 2-Me-4-CN—Ph

Notes for Table 3:

a) CI-HRMS: Calcd:367.2610, Found: 367.2607 (M+H);

b) CI-HRMS: Calcd:384.2400, Found: 384.2393 (M+H);

c) CI-HRMS: Calcd:404.1853, Found: 404.1844 (M+H);

d) CI-HRMS: Calcd:381.1594, Found: 381.1596 (M+H); Analysis: Calcd: C, 63.07, H, 5.57, N, 22.07, Cl, 9.32; Found: C, 63.40, H, 5.55, N, 21.96, Cl: 9.15

e) CI-HRMS: Calcd:369.1594, Found: 369.1576 (M+H);

f) CI-HRMS: Calcd:354.2216, Found: 354.2211 (M+H);

g) CI-HRMS: Calcd:410.1072, Found: 410.1075 (M+H);

h) CI-HRMS: Calcd:414.2427, Found: 414.2427(M+H);

i) CI-HRMS: Calcd:368.2372, Found: 368.2372(M+H);

j) CI-HRMS: Calcd:384.1955, Found: 384.1947(M+H);

k) CI-HRMS: Calcd:391.2168, Found: 391.2160(M+H);

l) CI-HRMS: Calcd:335.1984, Found: 335.1961(M+H);

m) CI-HRMS: Calcd:382.0759, Found: 382.0765(M+H);

n) NH₃-CI MS: Calcd: 360, Found: 360 (M+H)+

o) NH₃-CI MS: Calcd: 374, Found: 374 (M+H)+; NMR (CDCl₃, 300 MHz):δ7.29 (d, J=8.4 Hz, 1H), 7.04 (dd, J=1.8, 8 Hz, 1H), 6.96 (d, J=1.8 Hz, 1H), 6.15 (d, J=10, 1H), 4.19 (m, 1H), 3.81 (s, 3H), 2.47 (s, 3H), 2.32 (s, 3H), 1.65 (m, 4H), 0.99 (t, J=7.32 Hz, 6H)

p) NH₃-CI MS: Calcd: 390, Found: 390 (M+H)+; NMR (CDCl₃, 300 MHz): δ7.28 (d, J=8 Hz, 1H), 7.03 (d, J=8 Hz, 1H), 6.96 (s, 1H), 6.52 (d, J=9 Hz, 1H), 4.36 (m, 1H), 3.8 (s, 3H), 3.55 (m, 2H), 3.39 (s, 3H), 2.47 (s, 3H), 2.32 (s, 3H), 1.76 (m, 2H), 1.01 (t, J=7.32 Hz, 3H).

q) CI-HRMS: Calcd: 354.2294, Found: 354.2279 (M+H)+

r) CI-HRMS: Calcd: 340.2137, Found: 340.2138 (M+H)+

s) CI-HRMS: Calcd: 436.1307, Found: 436.1296 (M+H)+

The examples delineated in TABLE 4 may be prepared by the methods outlined in Examples 1A, 1B, 432, 433, 434. Commonly used abbreviations are: Ph is phenyl, Pr is propyl, Me is methyl, Et is ethyl, Bu is butyl, Ex is Example, EtOAc is ethyl acetate.

TABLE 4

Ex. Z R₃ Ar mp (° C.) 631 C—Me NHCH(Et)₂ 2-Br-4,5-(MeO)₂Ph 160–161 632 C—Me NHCH(Et)₂ 2-Br-4-MeOPh 110–111 633 C—Me N(CH₂CH₂OMe)₂ 2-Br-4-MeOPh 74–76 634 C—Me NHCH(CH₂OMe)₂ 2-Br-4-MeOPh 128–130 635 C—Me N(Et)₂ 2-Me-4-ClPh 113–114 636 C—Me N(c-Pr)Et 2,4-Cl₂Ph 637 C—Me N(c-Pr)Et 2,4-Me₂Ph 638 C—Me N(c-Pr)Et 2,4,6-Me₃Ph 639 C—Me N(c-Pr)Et 2-Me-4-MeOPh 640 C—Me N(c-Pr)Et 2-Cl-4-MeOPh 641 C—Me N(c-Pr)Et 2-Cl-4-MePh 642 C—Me N(c-Pr)Et 2-Me-4-ClPh 643 C—Me NHCH(c-Pr)₂ 2,4-Cl₂—Ph 644 C—Me NHCH(c-Pr)₂ 2,4-Me₂—Ph 645 C—Me NHCH(c-Pr)₂ 2-Me-4-Cl—Ph 646 C—Me NHCH(c-Pr)₂ 2-Cl-4-Me—Ph 647 C—Me NHCH(c-Pr)₂ 2-Me-4-OMe—Ph 648 C—Me NHCH(c-Pr)₂ 2-Cl-4-OMe—Ph 649 C—Me NHCH(CH₂OMe)₂ 2-Cl-5-F-OMePh 650 C—Me NEt₂ 2-Cl-5-F-OMePh 651 C—Me N(c-Pr)CH₂CH₂CN 2-Cl-5-F-OMePh 652 C—Me NHCH(Et)₂ 2-Cl-5-F-OMePh 653 C—Me N(CH₂CH₂OMe)₂ 2-Cl-5-F-OMePh 654 C—Me NEt₂ 2,6-Me₂-pyrid-3-yl 655 C—Me N(c-Pr)CH₂CH₂CN 2,6-Me₂-pyrid-3-yl 656 C—Me NHCH(Et)₂ 2,6-Me₂-pyrid-3-y1 657 C—Me N(CH₂CH₂OMe)₂ 2,6-Me₂-pyrid-3-yl 658 C—OH NHCH(CH₂OMe)₂ 2,4-Me₂—Ph 659 C—OH NEt₂ 2,4-Me₂—Ph 660 C—OH N(c-Pr)CH₂CH₂CN 2,4-Me₂—Ph 661 C—OH NHCH(Et)₂ 2,4-Me₂—Ph 662 C—OH N(CH₂CH₂OMe)₂ 2,4-Me₂—Ph 663 C—NEt₂ NHCH(CH₂OMe)₂ 2,4-Me₂—Ph 664 C—NEt₂ NEt₂ 2,4-Me₂—Ph 665 C—NEt₂ N(c-Pr)CH₂CH₂CN 2,4-Me₂—Ph 666 C—NEt₂ NHCH(Et)₂ 2,4-Me₂—Ph 667 C—NEt₂ N(CH₂CH₂OMe)₂ 2,4-Me₂—Ph 668 C—Me NHCH(Et)₂ 2-Me-4-CN—Ph 669 C—Me N(CH₂CH₂OMe)₂ 2-Me-4-CN—Ph

The examples in Tables 5 or 6 may be prepared by the methods illustrated in Examples 1A, 1B, 2, 3, 6, 431, 432, 433, 434 or by appropriate combinations thereof. Commonly used abbreviations are: Ph is phenyl, Pr is propyl, Me is methyl, Et is ethyl, Bu is butyl, Ex is Example.

TABLE 5

Ex. R₁₄ R₃ Ar 670 Me NHCH(CH₂OMe)₂ 2,4-Cl₂—Ph 671 Me NHCHPr₂ 2,4-Cl₂—Ph 672 Me NEtBu 2,4-Cl₂—Ph 673 Me NPr(CH₂-c-C₃H₅) 2,4-Cl₂—Ph 674 Me N(CH₂CH₂OMe)₂ 2,4-Cl₂—Ph 675 Me NH-3-heptyl 2,4-Cl₂—Ph 676 Me NHCH(Et)CH₂OMe 2,4-Cl₂—Ph 677 Me NEt₂ 2,4-Cl₂—Ph 678 Me NHCH(CH₂OEt)₂ 2,4-Cl₂—Ph 679 Me NH-3-pentyl 2,4-Cl₂—Ph 680 Me NMePh 2,4-Cl₂—Ph 681 Me NPr₂ 2,4-Cl₂—Ph 682 Me NH-3-hexyl 2,4-Cl₂—Ph 683 Me morpholino 2,4-Cl₂—Ph 684 Me N(CH₂Ph)CH₂CH₂OMe 2,4-Cl₂—Ph 685 Me NHCH(CH₂Ph)CH₂OMe 2,4-Cl₂—Ph 686 Me NH-4-tetrahydropyranyl 2,4-Cl₂—Ph 687 Me NH-cyclopentyl 2,4-Cl₂—Ph 688 Me OEt 2,4-Cl₂—Ph 689 Me OCH(Et)CH₂OMe 2,4-Cl₂—Ph 690 Me OCH₂Ph 2,4-Cl₂—Ph 691 Me O-3-pentyl 2,4-Cl₂—Ph 692 Me SEt 2,4-Cl₂—Ph 693 Me S(O)Et 2,4-Cl₂—Ph 694 Me SO₂Et 2,4-Cl₂—Ph 695 Me Ph 2,4-Cl₂—Ph 696 Me 2-CF₃—Ph 2,4-Cl₂—Ph 697 Me 2-Ph—Ph 2,4-Cl₂—Ph 698 Me 3-pentyl 2,4-Cl₂—Ph 699 Me cyclobutyl 2,4-Cl₂—Ph 700 Me 3-pyridyl 2,4-Cl₂—Ph 701 Me CH(Et)CH₂CONMe₂ 2,4-Cl₂—Ph 702 Me CH(Et)CH₂CH₂NMe₂ 2,4-Cl₂—Ph 703 Me NHCH(CH₂OMe)₂ 2,4,6-Me₃—Ph 704 Me NHCHPr₂ 2,4,6-Me₃—Ph 705 Me NEtBu 2,4,6-Me₃—Ph 706 Me NPr(CH₂-c-C₃H₅) 2,4,6-Me₃—Ph 707 Me N(CH₂CH₂OMe)₂ 2,4,6-Me₃—Ph 708 Me NH-3-heptyl 2,4,6-Me₃—Ph 709 Me NHCH(Et)CH₂OMe 2,4,6-Me₃—Ph 710 Me NEt₂ 2,4,6-Me₃—Ph 711 Me NHCH(CH₂OEt)₂ 2,4,6-Me₃—Ph 712 Me NH-3-pentyl 2,4,6-Me₃—Ph 713 Me NMePh 2,4,6-Me₃—Ph 714 Me NPr₂ 2,4,6-Me₃—Ph 715 Me NH-3-hexyl 2,4,6-Me₃—Ph 716 Me morpholino 2,4,6-Me₃—Ph 717 Me N(CH₂Ph)CH₂CH₂OMe 2,4,6-Me₃—Ph 718 Me NHCH(CH₂Ph)CH₂OMe 2,4,6-Me₃—Ph 719 Me NH-4-tetrahydropyranyl 2,4,6-Me₃—Ph 720 Me NH-cyclopentyl 2,4,6-Me₃—Ph 721 Me OEt 2,4,6-Me₃—Ph 722 Me OCH(Et)CH₂OMe 2,4,6-Me₃—Ph 723 Me OCH₂Ph 2,4,6-Me₃—Ph 724 Me O-3-pentyl 2,4,6-Me₃—Ph 725 Me SEt 2,4,6-Me₃—Ph 726 Me S(O)Et 2,4,6-Me₃—Ph 727 Me SO₂Et 2,4,6-Me₃—Ph 728 Me CH(CO₂Et)₂ 2,4,6-Me₃—Ph 729 Me C(Et)(CO₂Et)₂ 2,4,6-Me₃—Ph 730 Me CH(Et)CH₂OH 2,4,6-Me₃—Ph 731 Me CH(Et)CH₂OMe 2,4,6-Me₃—Ph 732 Me CONMe₂ 2,4,6-Me₃—Ph 733 Me COCH₃ 2,4,6-Me₃—Ph 734 Me CH(OH)CH₃ 2,4,6-Me₃—Ph 735 Me C(OH)Ph-3-pyridyl 2,4,6-Me₃—Ph 736 Me Ph 2,4,6-Me₃—Ph 737 Me 2-Ph—Ph 2,4,6-Me₃—Ph 738 Me 3-pentyl 2,4,6-Me₃—Ph 739 Me cyclobutyl 2,4,6-Me₃—Ph 740 Me 3-pyridyl 2,4,6-Me₃—Ph 741 Me CH(Et)CH₂CONMe₂ 2,4,6-Me₃—Ph 742 Me CH(Et)CH₂CH₂NMe₂ 2,4,6-Me₃—Ph 743 Me NHCH(CH₂OMe)₂ 2,4-Me₂—Ph 744 Me N(CH₂CH₂OMe)₂ 2,4-Me₂—Ph 745 Me NHCH(Et)CH₂OMe 2,4-Me₂—Ph 746 Me NH-3-pentyl 2,4-Me₂—Ph 747 Me NEt₂ 2,4-Me₂—Ph 748 Me N(CH₂CN)₂ 2,4-Me₂—Ph 749 Me NHCH(Me) CH₂OMe 2,4-Me₂—Ph 750 Me OCH(Et)CH₂OMe 2,4-Me₂—Ph 751 Me NPr-c-C₃H₅ 2,4-Me₂—Ph 752 Me NHCH(Me)CH₂NMe₂ 2,4-Me₂—Ph 753 Me N(c-C₃H₅)CH₂CH₂CN 2,4-Me₂—Ph 754 Me N(Pr)CH₂CH₂CN 2,4-Me₂—Ph 755 Me N(Bu)CH₂CH₂CN 2,4-Me₂—Ph 756 Me NHCHPr₂ 2,4-Me₂—Ph 757 Me NEtBu 2,4-Me₂—Ph 758 Me NPr(CH₂-c-C₃H₅) 2,4-Me₂—Ph 759 Me NH-3-heptyl 2,4-Me₂—Ph 760 Me NEt₂ 2,4-Me₂—Ph 761 Me NHCH(CH₂OEt)₂ 2,4-Me₂—Ph 762 Me NH-3-pentyl 2,4-Me₂—Ph 763 Me NMePh 2,4-Me₂—Ph 764 Me NPr₂ 2,4-Me₂—Ph 765 Me NH-3-hexyl 2,4-Me₂—Ph 766 Me morpholino 2,4-Me₂—Ph 767 Me N(CH₂Ph)CH₂CH₂OMe 2,4-Me₂—Ph 768 Me NHCH(CH₂Ph)CH₂OMe 2,4-Me₂—Ph 769 Me NH-4-tetrahydropyranyl 2,4-Me₂—Ph 770 Me NH-cyclopentyl 2,4-Me₂—Ph 771 Me NHCH(CH₂OMe)₂ 2-Me-4-MeO—Ph 772 Me N(CH₂CH₂OMe)₂ 2-Me-4-MeO—Ph 773 Me NHCH(Et)CH₂OMe 2-Me-4-MeO—Ph 774 Me N(Pr)CH₂CH₂CN 2-Me-4-MeO—Ph 775 Me OCH(Et)CH₂OMe 2-Me-4-MeO—Ph 776 Me NHCH(CH₂OMe)₂ 2-Br-4-MeO—Ph 777 Me N(CH₂CH₂OMe)₂ 2-Br-4-MeO—Ph 778 Me NHCH(Et)CH₂OMe 2-Br-4-MeO—Ph 779 Me N(Pr)CH₂CH₂CN 2-Br-4-MeO—Ph 780 Me OCH(Et)CH₂OMe 2-Br-4-MeO—Ph 781 Me NHCH(CH₂OMe)₂ 2-Me-4-NMe₂—Ph 782 Me N(CH₂CH₂OMe)₂ 2-Me-4-NMe₂—Ph 783 Me NHCH(Et)CH₂OMe 2-Me-4-NMe₂—Ph 784 Me N(Pr)CH₂CH₂CN 2-Me-4-NMe₂—Ph 785 Me OCH(Et)CH₂OMe 2-Me-4-NMe₂—Ph 786 Me NHCH(CH₂OMe)₂ 2-Br-4-NMe₂—Ph 787 Me N(CH₂CH₂OMe)₂ 2-Br-4-NMe₂—Ph 788 Me NHCH(Et)CH₂OMe 2-Br-4-NMe₂—Ph 789 Me N(Pr)CH₂CH₂CN 2-Br-4-NMe₂—Ph 790 Me OCH(Et)CH₂OMe 2-Br-4-NMe₂—Ph 791 Me NHCH(CH₂OMe)₂ 2-Br-4-i-Pr—Ph 792 Me N(CH₂CH₂OMe)₂ 2-Br-4-i-Pr—Ph 793 Me NHCH(Et)CH₂OMe 2-Br-4-i-Pr—Ph 794 Me N(Pr)CH₂CH₂CN 2-Br-4-i-Pr—Ph 795 Me OCH(Et)CH₂OMe 2-Br-4-i-Pr—Ph 796 Me NHCH(CH₂OMe)₂ 2-Br-4-Me—Ph 797 Me N(CH₂CH₂OMe)₂ 2-Br-4-Me—Ph 798 Me NHCH(Et)CH₂OMe 2-Br-4-Me—Ph 799 Me N(Pr)CH₂CH₂CN 2-Br-4-Me—Ph 800 Me OCH(Et)CH₂OMe 2-Br-4-Me—Ph 801 Me NHCH(CH₂OMe)₂ 2-Me-4-Br—Ph 802 Me N(CH₂CH₂OMe)₂ 2-Me-4-Br—Ph 803 Me NHCH(Et)CH₂OMe 2-Me-4-Br—Ph 804 Me N(Pr)CH₂CH₂CN 2-Me-4-Br—Ph 805 Me OCH(Et)CH₂OMe 2-Me-4-Br—Ph 806 Me NHCH(CH₂OMe)₂ 2-Cl-4,6-Me₂—Ph 807 Me N(CH₂CH₂OMe)₂ 2-Cl-4,6-Me₂—Ph 808 Me NHCH(CH₂OMe)₂ 4-Br-2,6-(Me)₂—Ph 809 Me N(CH₂CH₂OMe)₂ 4-Br-2,6-(Me)₂—Ph 810 Me NHCH(CH₂OMe)₂ 4-i-Pr-2-SMe—Ph 811 Me N(CH₂CH₂OMe)₂ 4-i-Pr-2-SMe—Ph 812 Me NHCH(CH₂OMe)₂ 2-Br-4-CF₃—Ph 813 Me N(CH₂CH₂OMe)₂ 2-Br-4-CF₃—Ph 814 Me NHCH(CH₂OMe)₂ 2-Br-4,6-(MeO)₂—Ph 815 Me N(CH₂CH₂OMe)₂ 2-Br-4,6-(MeO)₂—Ph 816 Me NHCH(CH₂OMe)₂ 2-Cl-4,6-(MeO)₂—Ph 817 Me N(CH₂CH₂OMe)₂ 2-Cl-4,6-(MeO)₂—Ph 818 Me NHCH(CH₂OMe)₂ 2,6-(Me)₂-4-SMe—Ph 819 Me N(CH₂CH₂OMe)₂ 2,6-(Me)₂-4-SMe—Ph 820 Me NHCH(CH₂OMe)₂ 4-(COMe)-2-Br—Ph 821 Me N(CH₂CH₂OMe)₂ 4-(COMe)-2-Br—Ph 822 Me NHCH(CH₂OMe)₂ 2,4,6-Me₃-pyrid-3-yl 823 Me N(CH₂CH₂OMe)₂ 2,4,6-Me₃-pyrid-3-yl 824 Me NHCH(CH₂OMe)₂ 2,4-(Br)₂—Ph 825 Me N(CH₂CH₂OMe)₂ 2,4-(Br)₂—Ph 826 Me NHCH(CH₂OMe)₂ 4-i-Pr-2-SMe—Ph 827 Me N(CH₂CH₂OMe)₂ 4-i-Pr-2-SMe—Ph 828 Me NHCH(CH₂OMe)₂ 4-i-Pr-2-SO₂Me—Ph 829 Me N(CH₂CH₂OMe)₂ 4-i-Pr-2-SO₂Me—Ph 830 Me NHCH(CH₂OMe)₂ 2,6-(Me)₂-4-SMe—Ph 831 Me N(CH₂CH₂OMe)₂ 2,6-(Me)₂-4-SMe—Ph 832 Me NHCH(CH₂OMe)₂ 2,6-(Me)₂-4-SO₂Me—Ph 833 Me N(CH₂CH₂OMe)₂ 2,6-(Me)₂-4-SO₂Me—Ph 834 Me NHCH(CH₂OMe)₂ 2-I-4-i-Pr—Ph 835 Me N(CH₂CH₂OMe)₂ 2-I-4-i-Pr—Ph 836 Me NHCH(CH₂OMe)₂ 2-Br-4-N(Me)₂-6-MeO—Ph 837 Me N(CH₂CH₂OMe)₂ 2-Br-4-N(Me)₂-6-MeO—Ph 838 Me NEt₂ 2-Br-4-MeO—Ph 839 Me NH-3-pentyl 2-Br-4-MeO—Ph 840 Me NHCH(CH₂OMe)₂ 2-CN-4-Me—Ph 841 Me N(c-C₃H₅)CH₂CH₂CN 2,4,6-Me₃—Ph 842 Me NHCH(CH₂CH₂OMe)- 2-Me-4-Br—Ph CH₂OMe 843 Me NHCH(CH₂OMe)₂ 2,5-Me₂-4-MeO—Ph 844 Me N(CH₂CH₂OMe)₂ 2,5-Me₂-4-MeO—Ph 845 Me NH-3-pentyl 2,5-Me₂-4-MeO—Ph 846 Me NEt₂ 2,5-Me₂-4-MeO—Ph 847 Me NHCH(CH₂OMe)₂ 2-Cl-4-MePh 848 Me NCH(Et)CH₂OMe 2-Cl-4-MePh 849 Me N(CH₂CH₂OMe)₂ 2-Cl-4-MePh 850 Me (S)—NHCH(CH₂CH₂OMe)- 2-Cl-4-MePh CH₂OMe 851 Me N(c-C₃H₅)CH₂CH₂CN 2,5-Me₂-4-MeOPh 852 Me NEt₂ 2-Me-4-MeOPh 853 Me OEt 2-Me-4-MeOPh 854 Me (S)—NHCH(CH₂CH₂OMe)- 2-Me-4-MeOPh CH₂OMe 855 Me N(c-C₃H₅)CH₂CH₂CN 2-Me-4-MeOPh 856 Me NHCH(CH₂CH₂OEt)₂ 2-Me-4-MeOPh 857 Me N(c-C₃H₅) CH₂CH₂CN 2,4-Cl₂—Ph 858 Me NEt₂ 2-Me-4-ClPh 859 Me NH-3-pentyl 2-Me-4-ClPh 860 Me N(CH₂CH₂OMe)₂ 2-Me-4-ClPh 861 Me NHCH(CH₂OMe)₂ 2-Me-4-ClPh 862 Me NEt₂ 2-Me-4-ClPh 863 Me NEt₂ 2-Cl-4-MePh 864 Me NH-3-pentyl 2-Cl-4-MePh 865 Me NHCH(CH₂OMe)₂ 2-Cl-4-MeOPh 866 Me N(CH₂CH₂OMe)₂ 2-Cl-4-MeOPh 867 Me NHCH(Et)CH₂OMe 2-Cl-4-MeOPh 868 Me N(c-Pr)CH₂CH₂CN 2-Cl-4-MeOPh 869 Me NEt₂ 2-Cl-4-MeOPh 870 Me NH-3-pentyl 2-Cl-4-MeOPh 871 Me NHCH(Et)CH₂CH₂OMe 2-Cl-4-MeOPh 872 Me NHCH(Me)CH₂CH₂OMe 2-Cl-4-MeOPh 873 Me NHCH(Et)CH₂CH₂OMe 2-Br-4-MeOPh 874 Me NHCH(Me)CH₂CH₂OMe 2-Br-4-MeOPh 875 Me NHCH(Et)CH₂CH₂OMe 2-Me-4-MeOPh 876 Me NHCH(Me)CH₂CH₂OMe 2-Me-4-MeOPh 877 Me NHCH(CH₂OMe)₂ 2-Cl-4,5-(MeO)₂Ph 878 Me N(CH₂CH₂OMe)₂ 2-Cl-4,5-(MeO)₂Ph 879 Me NHCH(Et)CH₂OMe 2-Cl-4,5-(MeO)₂Ph 880 Me N(c-Pr)CH₂CH₂CN 2-Cl-4,5-(MeO)₂Ph 881 Me NEt₂ 2-Cl-4,5-(MeO)₂Ph 882 Me NH-3-pentyl 2-Cl-4,5-(MeO)₂Ph 883 Me NHCH(Et)CH₂CH₂OMe 2-Cl-4,5-(MeO)₂Ph 884 Me NHCH(Me)CH₂CH₂OMe 2-Cl-4,5-(MeO)₂Ph 885 Me NHCH(CH₂OMe)₂ 2-Br-4,5-(MeO)₂Ph 886 Me N(CH₂CH₂OMe)₂ 2-Br-4,5-(MeO)₂Ph 887 Me NHCH(Et)CH₂OMe 2-Br-4,5-(MeO)₂Ph 888 Me N(c-Pr)CH₂CH₂CN 2-Br-4,5-(MeO)₂Ph 889 Me NEt₂ 2-Br-4,5-(MeO)₂Ph 890 Me NH-3-pentyl 2-Br-4,5-(MeO)₂Ph 891 Me NHCH(CH₂OMe)₂ 2-Cl-4,6-(MeO)₂Ph 892 Me N(CH₂CH₂OMe)₂ 2-Cl-4,6-(MeO)₂Ph 893 Me NEt₂ 2-Cl-4,6-(MeO)₂Ph 894 Me NH-3-pentyl 2-Cl-4,6-(MeO)₂Ph 895 Me NHCH(CH₂OMe)₂ 2-Me-4,6-(MeO)₂Ph 896 Me N(CH₂CH₂OMe)₂ 2-Me-4,6-(MeO)₂Ph 897 Me NHCH(Et)CH₂OMe 2-Me-4,6-(MeO)₂Ph 898 Me NEt₂ 2-Me-4,6-(MeO)₂Ph 899 Me NH-3-pentyl 2-Me-4,6-(MeO)₂Ph 900 Me NHCH(Et)CH₂CH₂OMe 2-Me-4-MeOPh 901 Me NHCH(Me)CH₂CH₂OMe 2-Me-4-MeOPh 902 Me NHCH(CH₂OMe)₂ 2-MeO-4-MePh 903 Me N(CH₂CH₂OMe)₂ 2-MeO-4-MePh 904 Me NHCH(Et)CH₂OMe 2-MeO-4-MePh 905 Me N(c-Pr)CH₂CH₂CN 2-MeO-4-MePh 906 Me NEt₂ 2-MeO-4-MePh 907 Me NH-3-pentyl 2-MeO-4-MePh 908 Me NHCH(Et)CH₂CH₂OMe 2-MeO-4-MePh 909 Me NHCH(Me)CH₂CH₂OMe 2-MeO-4-MePh 910 Me NHCH(CH₂OMe)₂ 2-MeO-4-MePh 911 Me N(CH₂CH₂OMe)₂ 2-MeO-4-MePh 912 Me NHCH(Et)CH₂OMe 2-MeO-4-MePh 913 Me N(c-Pr)CH₂CH₂CN 2-MeO-4-MePh 914 Me NEt₂ 2-MeO-4-MePh 915 Me NH-3-pentyl 2-MeO-4-MePh 916 Me NHCH(CH₂OMe)₂ 2-MeO-4-ClPh 917 Me N(CH₂CH₂OMe)₂ 2-MeO-4-ClPh 918 Me NHCH(Et)CH₂OMe 2-MeO-4-ClPh 919 Me NEt₂ 2-MeO-4-ClPh 920 Me NH-3-pentyl 2-MeO-4-ClPh

TABLE 6

Ex. R₁₄ R₃ Ar 921 Me NHCH(CH₂OMe)₂ 2,4-Cl₂—Ph 922 Me NHCHPr₂ 2,4-Cl₂—Ph 923 Me NEtBu 2,4-Cl₂—Ph 924 Me NPr(CH₂-c-C₃H₅) 2,4-Cl₂—Ph 925 Me N(CH₂CH₂OMe)₂ 2,4-Cl₂—Ph 926 Me NH-3-heptyl 2,4-Cl₂—Ph 927 Me NHCH(Et)CH₂OMe 2,4-Cl₂—Ph 928 Me NEt₂ 2,4-Cl₂—Ph 929 Me NHCH(CH₂OEt)₂ 2,4-Cl₂—Ph 930 Me NH-3-pentyl 2,4-Cl₂—Ph 931 Me NMePh 2,4-Cl₂—Ph 932 Me NPr₂ 2,4-Cl₂—Ph 933 Me NH-3-hexyl 2,4-Cl₂—Ph 934 Me morpholino 2,4-Cl₂—Ph 935 Me N(CH₂Ph)CH₂CH₂OMe 2,4-Cl₂—Ph 936 Me NHCH(CH₂Ph)CH₂OMe 2,4-Cl₂—Ph 937 Me NH-4-tetrahydropyranyl 2,4-Cl₂—Ph 938 Me NH-cyclopentyl 2,4-Cl₂—Ph 939 Me OEt 2,4-Cl₂—Ph 940 Me OCH(Et)CH₂OMe 2,4-Cl₂—Ph 941 Me OCH₂Ph 2,4-Cl₂—Ph 942 Me O-3-pentyl 2,4-Cl₂—Ph 943 Me SEt 2,4-Cl₂—Ph 944 Me S(O)Et 2,4-Cl₂—Ph 945 Me SO₂Et 2,4-Cl₂—Ph 946 Me Ph 2,4-Cl₂—Ph 947 Me 2-CF₃—Ph 2,4-Cl₂—Ph 948 Me 2-Ph—Ph 2,4-Cl₂—Ph 949 Me 3-pentyl 2,4-Cl₂—Ph 950 Me cyclobutyl 2,4-Cl₂—Ph 951 Me 3-pyridyl 2,4-Cl₂—Ph 952 Me CH(Et)CH₂CONMe₂ 2,4-Cl₂—Ph 953 Me CH(Et)CH₂CH₂NMe₂ 2,4-Cl₂—Ph 954 Me NHCH(CH₂OMe)₂ 2,4,6-Me₃—Ph 955 Me NHCHPr₂ 2,4,6-Me₃—Ph 956 Me NEtBu 2,4,6-Me₃—Ph 957 Me NPr(CH₂-c-C₃H₅) 2,4,6-Me₃—Ph 958 Me N(CH₂CH₂OMe)₂ 2,4,6-Me₃—Ph 959 Me NH-3-heptyl 2,4,6-Me₃—Ph 960 Me NHCH(Et)CH₂OMe 2,4,6-Me₃—Ph 961 Me NEt₂ 2,4,6-Me₃—Ph 962 Me NHCH(CH₂OEt)₂ 2,4,6-Me₃—Ph 963 Me NH-3-pentyl 2,4,6-Me₃—Ph 964 Me NMePh 2,4,6-Me₃—Ph 965 Me NPr₂ 2,4,6-Me₃—Ph 966 Me NH-3-hexyl 2,4,6-Me₃—Ph 967 Me morpholino 2,4,6-Me₃—Ph 968 Me N(CH₂Ph)CH₂CH₂OMe 2,4,6-Me₃—Ph 969 Me NHCH(CH₂Ph)CH₂OMe 2,4,6-Me₃—Ph 970 Me NH-4-tetrahydropyranyl 2,4,6-Me₃—Ph 971 Me NE-cyclopentyl 2,4,6-Me₃—Ph 972 Me OEt 2,4,6-Me₃—Ph 973 Me OCH(Et)CH₂OMe 2,4,6-Me₃—Ph 974 Me OCH₂Ph 2,4,6-Me₃—Ph 975 Me O-3-pentyl 2,4,6-Me₃—Ph 976 Me SEt 2,4,6-Me₃—Ph 977 Me S(O)Et 2,4,6-Me₃—Ph 978 Me SO₂Et 2,4,6-Me₃—Ph 979 Me CH(CO₂Et)₂ 2,4,6-Me₃—Ph 980 Me C(Et)(CO₂Et)₂ 2,4,6-Me₃—Ph 981 Me CH(Et)CH₂OH 2,4,6-Me₃—Ph 982 Me CH(Et)CH₂OMe 2,4,6-Me₃—Ph 983 Me CONMe₂ 2,4,6-Me₃—Ph 984 Me COCH₃ 2,4,6-Me₃—Ph 985 Me CH(OH)CH₃ 2,4,6-Me₃—Ph 986 Me C(OH)Ph-3-pyridyl 2,4,6-Me₃—Ph 987 Me Ph 2,4,6-Me₃—Ph 988 Me 2-Ph—Ph 2,4,6-Me₃—Ph 989 Me 3-pentyl 2,4,6-Me₃—Ph 990 Me cyclobutyl 2,4,6-Me₃—Ph 991 Me 3-pyridyl 2,4,6-Me₃—Ph 992 Me CH(Et)CH₂CONMe₂ 2,4,6-Me₃—Ph 993 Me CH(Et)CH₂CH₂NMe₂ 2,4,6-Me₃—Ph 994 Me NHCH(CH₂OMe)₂ 2,4-Me₂—Ph 995 Me N(CH₂CH₂OMe)₂ 2,4-Me₂—Ph 996 Me NHCH(Et)CH₂OMe 2,4-Me₂—Ph 997 Me NH-3-pentyl 2,4-Me₂—Ph 998 Me NEt₂ 2,4-Me₂—Ph 999 Me N(CH₂CN)₂ 2,4-Me₂—Ph 1000 Me NHCH(Me)CH₂OMe 2,4-Me₂—Ph 1001 Me OCH(Et)CH₂OMe 2,4-Me₂—Ph 1002 Me NPr-c-C₃H₅ 2,4-Me₂—Ph 1003 Me NHCH(Me)CH₂NMe₂ 2,4-Me₂—Ph 1004 Me N(c-C₃H₅)CH₂CH₂CN 2,4-Me₂—Ph 1005 Me N(Pr)CH₂CH₂CN 2,4-Me₂—Ph 1006 Me N(Bu)CH₂CH₂CN 2,4-Me₂—Ph 1007 Me NHCHPr₂ 2,4-Me₂—Ph 1008 Me NEtBu 2,4-Me₂—Ph 1009 Me NPr(CH₂-c-C₃H₅) 2,4-Me₂—Ph 1010 Me NH-3-heptyl 2,4-Me₂—Ph 1011 Me NEt₂ 2,4-Me₂—Ph 1012 Me NHCH(CH₂OEt)₂ 2,4-Me₂—Ph 1013 Me NH-3-pentyl 2,4-Me₂—Ph 1014 Me NMePh 2,4-Me₂—Ph 1015 Me NPr₂ 2,4-Me₂—Ph 1016 Me NH-3-hexyl 2,4-Me₂—Ph 1017 Me morpholino 2,4-Me₂—Ph 1018 Me N(CH₂Ph)CH₂CH₂OMe 2,4-Me₂—Ph 1019 Me NHCH(CH₂Ph)CH₂OMe 2,4-Me₂—Ph 1020 Me NH-4-tetrahydropyranyl 2,4-Me₂—Ph 1021 Me NH-cyclopentyl 2,4-Me₂—Ph 1022 Me NHCH(CH₂OMe)₂ 2-Me-4-MeO—Ph 1023 Me N(CH₂CH₂OMe)₂ 2-Me-4-MeO—Ph 1024 Me NHCH(Et)CH₂OMe 2-Me-4-MeO—Ph 1025 Me N(Pr)CH₂CH₂CN 2-Me-4-MeO—Ph 1026 Me OCH(Et)CH₂OMe 2-Me-4-MeO—Ph 1027 Me NHCH(CH₂OMe)₂ 2-Br-4-MeO—Ph 1028 Me N(CH₂CH₂OMe)₂ 2-Br-4-MeO—Ph 1029 Me NHCH(Et)CH₂OMe 2-Br-4-MeO—Ph 1030 Me N(Pr)CH₂CH₂CN 2-Br-4-MeO—Ph 1031 Me OCH(Et)CH₂OMe 2-Br-4-MeO—Ph 1032 Me NHCH(CH₂OMe)₂ 2-Me-4-NMe₂—Ph 1033 Me N(CH₂CH₂OMe)₂ 2-Me-4-NMe₂—Ph 1034 Me NHCH(Et)CH₂OMe 2-Me-4-NMe₂—Ph 1035 Me N(Pr)CH₂CH₂CN 2-Me-4-NMe₂—Ph 1036 Me OCH(Et)CH₂OMe 2-Me-4-NMe₂—Ph 1037 Me NHCH(CH₂OMe)₂ 2-Br-4-NMe₂—Ph 1038 Me N(CH₂CH₂OMe)₂ 2-Br-4-NMe₂—Ph 1039 Me NHCH(Et)CH₂OMe 2-Br-4-NMe₂—Ph 1040 Me N(Pr)CH₂CH₂CN 2-Br-4-NMe₂—Ph 1041 Me OCH(Et)CH₂OMe 2-Br-4-NMe₂—Ph 1042 Me NHCH(CH₂OMe)₂ 2-Br-4-i-Pr—Ph 1043 Me N(CH₂CH₂OMe)₂ 2-Br-4-i-Pr—Ph 1044 Me NHCH(Et)CH₂OMe 2-Br-4-i-Pr—Ph 1045 Me N(Pr)CH₂CH₂CN 2-Br-4-i-Pr—Ph 1046 Me OCH(Et)CH₂OMe 2-Br-4-i-Pr—Ph 1047 Me NHCH(CH₂OMe)₂ 2-Br-4-Me—Ph 1048 Me N(CH₂CH₂OMe)₂ 2-Br-4-Me—Ph 1049 Me NHCH(Et)CH₂OMe 2-Br-4-Me—Ph 1050 Me N(Pr)CH₂CH₂CN 2-Br-4-Me—Ph 1051 Me OCH(Et)CH₂OMe 2-Br-4-Me—Ph 1052 Me NHCH(CH₂OMe)₂ 2-Me-4-Br—Ph 1053 Me N(CH₂CH₂OMe)₂ 2-Me-4-Br—Ph 1054 Me NHCH(Et)CH₂OMe 2-Me-4-Br—Ph 1055 Me N(Pr)CH₂CH₂CN 2-Me-4-Br—Ph 1056 Me OCH(Et)CH₂OMe 2-Me-4-Br—Ph 1057 Me NHCH(CH₂OMe)₂ 2-Cl-4,6-Me₂—Ph 1058 Me N(CH₂CH₂OMe)₂ 2-Cl-4,6-Me₂—Ph 1059 Me NHCH(CH₂OMe)₂ 4-Br-2,6-(Me)₂—Ph 1060 Me N(CH₂CH₂OMe)₂ 4-Br-2,6-(Me)₂—Ph 1061 Me NHCH(CH₂OMe)₂ 4-i-Pr-2-SMe—Ph 1062 Me N(CH₂CH₂OMe)₂ 4-i-Pr-2-SMe—Ph 1063 Me NHCH(CH₂OMe)₂ 2-Br-4-CF₃—Ph 1064 Me N(CH₂CH₂OMe)₂ 2-Br-4-CF₃—Ph 1065 Me NHCH(CH₂OMe)₂ 2-Br-4,6-(MeO)₂—Ph 1066 Me N(CH₂CH₂OMe)₂ 2-Br-4,6-(MeO)₂—Ph 1067 Me NHCH(CH₂OMe)₂ 2-Cl-4,6-(MeO)₂—Ph 1068 Me N(CH₂CH₂OMe)₂ 2-Cl-4,6-(MeO)₂—Ph 1069 Me NHCH(CH₂OMe)₂ 2,6-(Me)₂-4-SMe—Ph 1070 Me N(CH₂CH₂OMe)₂ 2,6-(Me)₂-4-SMe—Ph 1071 Me NHCH(CH₂OMe)₂ 4-(COMe)-2-Br—Ph 1072 Me N(CH₂CH₂OMe)₂ 4-(COMe)-2-Br—Ph 1073 Me NHCH(CH₂OMe)₂ 2,4,6-Me₃-pyrid-3-yl 1074 Me N(CH₂CH₂OMe)₂ 2,4,6-Me₃-pyrid-3-yl 1075 Me NHCH(CH₂OMe)₂ 2,4-(Br)₂—Ph 1076 Me N(CH₂CH₂OMe)₂ 2,4-(Br)₂—Ph 1077 Me NHCH(CH₂OMe)₂ 4-i-Pr-2-SMe—Ph 1078 Me N(CH₂CH₂OMe)₂ 4-i-Pr-2-SMe—Ph 1079 Me NHCH(CH₂OMe)₂ 4-i-Pr-2-SO₂Me—Ph 1080 Me N(CH₂CH₂OMe)₂ 4-i-Pr-2-SO₂Me—Ph 1081 Me NHCH(CH₂OMe)₂ 2,6-(Me)₂-4-SMe—Ph 1082 Me N(CH₂CH₂OMe)₂ 2,6-(Me)₂-4-SMe—Ph 1083 Me NHCH(CH₂OMe)₂ 2,6-(Me)₂-4-SO₂Me—Ph 1084 Me N(CH₂CH₂OMe)₂ 2,6-(Me)₂-4-SO₂Me—Ph 1085 Me NHCH(CH₂OMe)₂ 2-I-4-i-Pr—Ph 1086 Me N(CH₂CH₂OMe)₂ 2-I-4-i-Pr—Ph 1087 Me NHCH(CH₂OMe)₂ 2-Br-4-N(Me)₂-6-MeO—Ph 1088 Me N(CH₂CH₂OMe)₂ 2-Br-4-N(Me)₂-6-MeO—Ph 1089 Me NEt₂ 2-Br-4-MeO—Ph 1090 Me NH-3-pentyl 2-Br-4-MeO—Ph 1091 Me NHCH(CH₂OMe)₂ 2-CN-4-Me—Ph 1092 Me N(c-C₃H₅)CH₂CH₂CN 2,4,6-Me₃—Ph 1093 Me NHCH(CH₂CH₂OMe) 2-Me-4-Br—Ph CH₂OMe 1094 Me NHCH(CH₂OMe)₂ 2,5-Me₂-4-MeO—Ph 1095 Me N(CH₂CH₂OMe)₂ 2,5-Me₂-4-MeO—Ph 1096 Me NH-3-pentyl 2,5-Me₂-4-MeO—Ph 1097 Me NEt₂ 2,5-Me₂-4-MeO—Ph 1098 Me NHCH(CH₂OMe)₂ 2-Cl-4-MePh 1099 Me NCH(Et)CH₂OMe 2-Cl-4-MePh 1100 Me N(CH₂CH₂OMe)₂ 2-Cl-4-MePh 1101 Me (S)-NHCH(CH₂CH₂OMe) 2-Cl-4-MePh CH₂OMe 1102 Me N(c-C₃H₅)CH₂CH₂CN 2,5-Me₂-4-MeOPh 1103 Me NEt₂ 2-Me-4-MeOPh 1104 Me OEt 2-Me-4-MeOPh 1105 Me (S)-NHCH(CH₂CH₂OMe) 2-Me-4-MeOPh CH₂OMe 1106 Me N(c-C₃H₅)CH₂CH₂CN 2-Me-4-MeOPh 1107 Me NHCH(CH₂CH₂OEt)₂ 2-Me-4-MeOPh 1108 Me N(c-C₃H₅)CH₂CH₂CN 2,4-Cl₂—Ph 1109 Me NEt₂ 2-Me-4-ClPh 1110 Me NH-3-pentyl 2-Me-4-ClPh 1111 Me N(CH₂CH₂OMe)₂ 2-Me-4-ClPh 1112 Me NHCH(CH₂OMe)₂ 2-Me-4-ClPh 1113 Me NEt₂ 2-Me-4-ClPh 1114 Me NEt₂ 2-Cl-4-MePh 1115 Me NH-3-pentyl 2-Cl-4-MePh 1116 Me NHCH(CH₂OMe)₂ 2-Cl-4-MeOPh 1117 Me N(CH₂CH₂OMe)₂ 2-Cl-4-MeOPh 1118 Me NHCH(Et)CH₂OMe 2-Cl-4-MeOPh 1119 Me N(c-Pr)CH₂CH₂CN 2-Cl-4-MeOPh 1120 Me NEt₂ 2-Cl-4-MeOPh 1121 Me NH-3-pentyl 2-Cl-4-MeOPh 1123 Me NHCH(Et)CH₂CH₂OMe 2-Cl-4-MeOPh 1124 Me NHCH(Me)CH₂CH₂OMe 2-Cl-4-MeOPh 1125 Me NHCH(Et)CH₂CH₂OMe 2-Br-4-MeOPh 1126 Me NHCH(Me)CH₂CH₂OMe 2-Br-4-MeOPh 1127 Me NHCH(Et)CH₂CH₂OMe 2-Me-4-MeOPh 1128 Me NHCH(Me)CH₂CH₂OMe 2-Me-4-MeOPh 1129 Me NHCH(CH₂OMe)₂ 2-Cl-4,5-(MeO)₂Ph 1130 Me N(CH₂CH₂OMe)₂ 2-Cl-4,5-(MeO)₂Ph 1131 Me NHCH(Et)CH₂OMe 2-Cl-4,5-(MeO)₂Ph 1132 Me N(c-Pr)CH₂CH₂CN 2-Cl-4,5-(MeO)₂Ph 1133 Me NEt₂ 2-Cl-4,5-(MeO)₂Ph 1134 Me NH-3-pentyl 2-Cl-4,5-(MeO)₂Ph 1135 Me NHCH(Et)CH₂CH₂OMe 2-Cl-4,5-(MeO)₂Ph 1136 Me NHCH(Me)CH₂CH₂OMe 2-Cl-4,5-(MeO)₂Ph 1137 Me NHCH(CH₂OMe)₂ 2-Br-4,5-(MeO)₂Ph 1138 Me N(CH₂CH₂OMe)₂ 2-Br-4,5-(MeO)₂Ph 1139 Me NHCH(Et)CH₂OMe 2-Br-4,5-(MeO)₂Ph 1140 Me N(c-Pr)CH₂CH₂CN 2-Br-4,5-(MeO)₂Ph 1141 Me NEt₂ 2-Br-4,5-(MeO)₂Ph 1142 Me NH-3-pentyl 2-Br-4,5-(MeO)₂Ph 1143 Me NHCH(CH₂OMe)₂ 2-Cl-4,6-(MeO)₂Ph 1144 Me N(CH₂CH₂OMe)₂ 2-Cl-4,6-(MeO)₂Ph 1145 Me NEt₂ 2-Cl-4,6-(MeO)₂Ph 1146 Me NH-3-pentyl 2-Cl-4,6-(MeO)₂Ph 1147 Me NHCH(CH₂OMe)₂ 2-Me-4,6-(MeO)₂Ph 1148 Me N(CH₂CH₂OMe)₂ 2-Me-4,6-(MeO)₂Ph 1149 Me NHCH(Et)CH₂OMe 2-Me-4,6-(MeO)₂Ph 1150 Me NEt₂ 2-Me-4,6-(MeO)₂Ph 1151 Me NH-3-pentyl 2-Me-4,6-(MeO)₂Ph 1152 Me NHCH(Et)CH₂CH₂OMe 2-Me-4-MeOPh 1153 Me NHCH(Me)CH₂CH₂OMe 2-Me-4-MeOPh 1154 Me NHCH(CH₂OMe)₂ 2-MeO-4-MePh 1155 Me N(CH₂CH₂OMe)₂ 2-MeO-4-MePh 1156 Me NHCH(Et)CH₂OMe 2-MeO-4-MePh 1157 Me N(c-Pr)CH₂CH₂CN 2-MeO-4-MePh 1158 Me NEt₂ 2-MeO-4-MePh 1159 Me NH-3-pentyl 2-MeO-4-MePh 1160 Me NHCH(Et)CH₂CH₂OMe 2-MeO-4-MePh 1161 Me NHCH(Me)CH₂CH₂OMe 2-MeO-4-MePh 1162 Me NHCH(CH₂OMe)₂ 2-MeO-4-MePh 1163 Me N(CH₂CH₂OMe)₂ 2-MeO-4-MePh 1164 Me NHCH(Et)CH₂OMe 2-MeO-4-MePh 1165 Me N(c-Pr)CH₂CH₂CN 2-MeO-4-MePh 1166 Me NEt₂ 2-MeO-4-MePh 1167 Me NH-3-pentyl 2-MeO-4-MePh 1168 Me NHCH(CH₂OMe)₂ 2-MeO-4-ClPh 1169 Me N(CH₂CH₂OMe)₂ 2-MeO-4-ClPh 1170 Me NHCH(Et)CH₂OMe 2-MeO-4-ClPh 1171 Me NEt₂ 2-MeO-4-ClPh 1172 Me NH-3-pentyl 2-MeO-4-ClPh

Utility

CRF-R1 Receptor Binding Assay for the Evaluation of Biological Activity

The following is a description of the isolation of cell membranes containing cloned human CRF-R1 receptors for use in the standard binding assay as well as a description of the assay itself.

Messenger RNA was isolated from human hippocampus. The mRNA was reverse transcribed using oligo (dt) 12–18 and the coding region was amplified by PCR from start to stop codons. The resulting PCR fragment was cloned into the EcoRV site of pGEMV, from whence the insert was reclaimed using XhoI+XbaI and cloned into the XhoI+XbaI sites of vector pm3ar (which contains a CMV promoter, the SV40 ‘t’ splice and early poly A signals, an Epstein-Barr viral origin of replication, and a hygromycin selectable marker). The resulting expression vector, called phchCRFR was transfected in 293EBNA cells and cells retaining the episome were selected in the presence of 400 μM hygromycin. Cells surviving 4 weeks of selection in hygromycin were pooled, adapted to growth in suspension and used to generate membranes for the binding assay described below. Individual aliquots containing approximately 1×10⁸ of the suspended cells were then centrifuged to form a pellet and frozen.

For the binding assay a frozen pellet described above containing 293EBNA cells transfected with hCRFR1 receptors is homogenized in 10 ml of ice cold tissue buffer (50 mM HEPES buffer pH 7.0, containing 10 mM MgCl₂, 2 mM EGTA, 1 μg/l aprotinin, 1 μg/ml leupeptin and 1 μg/ml pepstatin). The homogenate is centrifuged at 40,000×g for 12 min and the resulting pellet rehomogenized in 10 ml of tissue buffer. After another centrifugation at 40,000×g for 12 min, the pellet is resuspended to a protein concentration of 360 μg/ml to be used in the assay.

Binding assays are performed in 96 well plates; each well having a 300 μl capacity. To each well is added 50 μl of test drug dilutions (final concentration of drugs range from 10⁻¹⁰–10⁻⁵ M), 100 μl of ¹²⁵I-ovine-CRF (¹²⁵I-o-CRF) (final concentration 150 pM) and 150 μl of the cell homogenate described above. Plates are then allowed to incubate at room temperature for 2 hours before filtering the incubate over GF/F filters (presoaked with 0.3% polyethyleneimine) using an appropriate cell harvester. Filters are rinsed 2 times with ice cold assay buffer before removing individual filters and assessing them for radioactivity on a gamma counter.

Curves of the inhibition of ¹²⁵I-o-CRF binding to cell membranes at various dilutions of test drug are analyzed by the iterative curve fitting program LIGAND [P. J. Munson and D. Rodbard, Anal. Biochem. 107:220 (1980), which provides Ki values for inhibition which are then used to assess biological activity.

A compound is considered to be active if it has a K_(i) value of less than about 10000 nM for the inhibition of CRF.

Inhibition of CRF-Stimulated Adenylate Cyclase Activity

Inhibition of CRF-stimulated adenylate cyclase activity can be performed as described by G. Battaglia et al. Synapse 1:572 (1987). Briefly, assays are carried out at 37° C. for 10 min in 200 ml of buffer containing 100 mM Tris-HCl (pH 7.4 at 37° C.), 10 mM MgCl₂, 0.4 mM EGTA, 0.1% BSA, 1 mM isobutylmethylxanthine (IBMX), 250 units/ml phosphocreatine kinase, 5 mM creatine phosphate, 100 mM guanosine 5′-triphosphate, 100 nM oCRF, antagonist peptides (concentration range 10⁻⁹ to 10^(6m)) and 0.8 mg original wet weight tissue (approximately 40–60 mg protein). Reactions are initiated by the addition of 1 mM ATP/³²P]ATP (approximately 2–4 mCi/tube) and terminated by the addition of 100 ml of 50 mM Tris-HCL, 45 mM ATP and 2% sodium dodecyl sulfate. In order to monitor the recovery of cAMP, 1 μl of [³H]cAMP (approximately 40,000 dpm) is added to each tube prior to separation. The separation of [³²P]cAMP from [³²P]ATP is performed by sequential elution over Dowex and alumina columns.

In vivo Biological Assay

The in vivo activity of the compounds of the present invention can be assessed using any one of the biological assays available and accepted within the art. Illustrative of these tests include the Acoustic Startle Assay, the Stair Climbing Test, and the Chronic Administration Assay. These and other models useful for the testing of compounds of the present invention have been outlined in C. W. Berridge and A. J. Dunn Brain Research Reviews 15:71 (1990).

Compounds may be tested in any species of rodent or small mammal.

Compounds of this invention have utility in the treatment of inbalances associated with abnormal levels of corticotropin releasing factor in patients suffering from depression, affective disorders, and/or anxiety.

Compounds of this invention can be administered to treat these abnormalities by means that produce contact of the active agent with the agent's site of action in the body of a mammal. The compounds can be administered by any conventional means available for use in conjunction with pharmaceuticals either as individual therapeutic agent or in combination of therapeutic agents. They can be administered alone, but will generally be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

The dosage administered will vary depending on the use and known factors such as pharmacodynamic character of the particular agent, and its mode and route of administration; the recipient's age, weight, and health; nature and extent of symptoms; kind of concurrent treatment; frequency of treatment; and desired effect. For use in the treatment of said diseases or conditions, the compounds of this invention can be orally administered daily at a dosage of the active ingredient of 0.002 to 200 mg/kg of body weight. Ordinarily, a dose of 0.01 to 10 mg/kg in divided doses one to four times a day, or in sustained release formulation will be effective in obtaining the desired pharmacological effect.

Dosage forms (compositions) suitable for administration contain from about 1 mg to about 100 mg of active ingredient per unit. In these pharmaceutical compositions, the active ingredient will ordinarily be present in an amount of about 0.5 to 95% by weight based on the total weight of the composition.

The active ingredient can be administered orally is solid dosage forms, such as capsules, tablets and powders; or in liquid forms such as elixirs, syrups, and/or suspensions. The compounds of this invention can also be administered parenterally in sterile liquid dose formulations.

Gelatin capsules can be used to contain the active ingredient and a suitable carrier such as but not limited to lactose, starch, magnesium stearate, steric acid, or cellulose derivatives. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of time. Compressed tablets can be sugarcoated or film-coated to mask any unpleasant taste, or used to protect the active ingredients from the atmosphere, or to allow selective disintegration of the tablet in the gastrointestinal tract.

Liquid dose forms for oral administration can contain coloring or flavoring agents to increase patient acceptance.

In general, water, pharmaceutically acceptable oils, saline, aqueous dextrose (glucose), and related sugar solutions and glycols, such as propylene glycol or polyethylene glycol, are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, butter substances. Antioxidizing agents, such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or in combination, are suitable stabilizing agents. Also used are citric acid and its salts, and EDTA. In addition, parenteral solutions can contain preservatives such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.

Suitable pharmaceutical carriers are described in “Remington's Pharmaceutical Sciences”, A. Osol, a standard reference in the field.

Useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows:

Capsules

A large number of units capsules are prepared by filling standard two-piece hard gelatin capsules each with 100 mg of powdered active ingredient, 150 mg lactose, 50 mg cellulose, and 6 mg magnesium stearate.

Soft Gelatin Capsules

A mixture of active ingredient in a digestible oil such as soybean, cottonseed oil, or olive oil is prepared and injected by means of a positive displacement was pumped into gelatin to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules were washed and dried.

Tablets

A large number of tablets are prepared by conventional procedures so that the dosage unit was 100 mg active ingredient, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch, and 98.8 mg lactose. Appropriate coatings may be applied to increase palatability or delayed adsorption.

The compounds of this invention may also be used as reagents or standards in the biochemical study of neurological function, dysfunction, and disease.

Although the present invention has been described and exemplified in terms of certain preferred embodiments, other embodiments will be apparent to those skilled in the art. The invention is, therefore, not limited to the particular embodiments described and exemplified, but is capable of modification or variation without departing from the spirit of the invention, the full scope of which is delineated by the appended claims. 

1. A method of treating supranuclear palsy in mammals comprising administering to the mammal a therapeutically effective amount of a compound of Formula (2):

and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt forms thereof, wherein: Ar is 2,3-dihydrobenzofuranyl; R¹ is CN; R¹ is H; and R¹⁴ is C₃–C₁₀ alkynyl. 